Language：English   Publishing type：Research paper (scientific journal)  

We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% [95% CI: -49.2%, -9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

DOI： 10.1038/s41746-024-01114-8

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Single-nucleotide polymorphisms (SNP) of ATP2B1 gene are associated with essential hypertension but their association with resistant hypertension (RHT) remains unexplored. The authors examined the relationship between ATP2B1 SNPs and RHT by genotyping 12 SNPs in ATP2B1 gene of 1124 Japanese individuals with lifestyle-related diseases. Patients with RHT had inadequate blood pressure (BP) control using three antihypertensive drugs or used ≥4 antihypertensive drugs. Patients with controlled hypertension had BP controlled using ≤3 antihypertensive drugs. The association between each SNP and RHT was analyzed by logistic regression. The final cohort had 888 (79.0%) and 43 (3.8%) patients with controlled hypertension and RHT, respectively. Compared with patients homozygous for the minor allele of each SNP in ATP2B1, a significantly higher number of patients carrying the major allele at 10 SNPs exhibited RHT (most significant at rs1401982: 5.8% vs. 0.8%, p = .014; least significant at rs11105378: 5.7% vs. 0.9%, p = .035; most nonsignificant at rs12817819: 5.1% vs. 10%, p = .413). After multivariate adjustment for age, sex, systolic BP, and other confounders, the association remained significant for rs2681472 and rs1401982 (OR: 7.60, p < .05 and OR: 7.62, p = .049, respectively). Additionally, rs2681472 and rs1401982 were in linkage disequilibrium with rs11105378. This study identified two ATP2B1 SNPs associated with RHT in the Japanese population. rs1401982 was most closely associated with RHT, and major allele carriers of rs1401982 required significantly more antihypertensive medications. Analysis of ATP2B1 SNPs in patients with hypertension can help in early prediction of RHT and identification of high-risk patients who are more likely to require more antihypertensive medications.

DOI： 10.1111/jch.14785

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BACKGROUND: Increasing physical activity improves glycemic control in patients with type 2 diabetes (T2D). Mobile health (mHealth) interventions have been proven to increase exercise, but engagement often fades with time. As the use of health behavior theory in mHealth design can increase effectiveness, we developed StepAdd, an mHealth intervention based on the constructs of social cognitive theory (SCT). StepAdd improves exercise behavior self-efficacy and self-regulation through the use of goal-setting, barrier-identifying, and barrier-coping strategies, as well as automatic feedback functions. A single-arm pilot study of StepAdd among 33 patients with T2D showed a large increase in step count (mean change of 4714, SD 3638 daily steps or +86.7%), along with strong improvements in BMI (mean change of -0.3 kg/m2) and hemoglobin A1c level (mean change of -0.79 percentage points). OBJECTIVE: In this study, we aim to investigate the efficacy and safety of StepAdd, an mHealth exercise support system for patients with T2D, via a large, long, and controlled follow-up to the pilot study. METHODS: This is a randomized, open-label, multicenter study targeting 160 patients with T2D from 5 institutions in Japan with a 24-week intervention. The intervention group will record daily step counts, body weight, and blood pressure using the SCT-based mobile app, StepAdd, and receive feedback about these measurements. In addition, they will set weekly step count goals, identify personal barriers to walking, and define strategies to overcome these barriers. The control group will record daily step counts, body weight, and blood pressure using a non-SCT-based placebo app. Both groups will receive monthly consultations with a physician who will advise patients regarding lifestyle modifications and use of the app. The 24-week intervention period will be followed by a 12-week observational period to investigate the sustainability of the intervention's effects. The primary outcome is between-group difference in the change in hemoglobin A1c values at 24 weeks. The secondary outcomes include other health measures, measurements of steps, measurements of other behavior changes, and assessments of app use. The trial began in January 2023 and is intended to be completed in December 2025. RESULTS: As of September 5, 2023, we had recruited 44 patients. We expect the trial to be completed by October 8, 2025, with the follow-up observation period being completed by December 31, 2025. CONCLUSIONS: This trial will provide important evidence about the efficacy of an SCT-based mHealth intervention in improving physical activities and glycemic control in patients with T2D. If this study proves the intervention to be effective and safe, it could be a key step toward the integration of mHealth as part of the standard treatment received by patients with T2D in Japan. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCT) jRCT2032220603; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2032220603. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53514.

DOI： 10.2196/53514

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Background and Objectives: Omega-3 fatty acids have potent lipid-lowering and antiplatelet effects; however, randomized controlled trials have yet to examine the effect of high-dose omega-3 fatty acid administration on peripheral artery disease (PAD) in hemodialysis patients with dyslipidemia. Therefore, this study aimed to evaluate the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the ankle-brachial index (ABI) and remnant-like lipoprotein cholesterol (RLP-C) levels, which are indicators of PAD severity. Materials and Methods: Thirty-eight participants (mean age: 73.6 ± 12.7 years) were randomly assigned using stratified block randomization to either conventional therapy alone or conventional therapy supplemented with high-dose EPA/DHA (EPA: 1860 mg; DHA: 1500 mg) for a three-month intervention period. Patients in the conventional therapy alone group who opted to continue were provided with a low-dose EPA/DHA regimen (EPA: 930 mg; DHA: 750 mg) for an additional three months. The baseline and 3-month values for RLP-C, an atherogenic lipid parameter, and the ABI were recorded. Results: The results of the 3-month assessments revealed that the mean RLP-C changes were -3.25 ± 3.15 mg/dL and 0.44 ± 2.53 mg/dL in the EPA/DHA and control groups, respectively (p < 0.001), whereas the changes in the mean ABI values were 0.07 ± 0.11 and -0.02 ± 0.09 in the EPA/DHA and control groups, respectively (p = 0.007). In the EPA/DHA group, a significant negative correlation was found between the changes in RLP-C levels and the ABI (r = -0.475, p = 0.04). Additionally, the change in the RLP-C levels independently influenced the change in the ABI in the EPA/DHA group, even after adjusting for age, sex, and statin use (p = 0.042). Conclusions: Add-on EPA/DHA treatment improved the effectiveness of conventional therapy (such as statin treatment) for improving the ABI in hemodialysis patients with dyslipidemia by lowering RLP-C levels. Therefore, clinicians involved in dialysis should focus on RLP-C when considering residual cardiovascular disease risk in hemodialysis patients and should consider screening patients with elevated levels.

DOI： 10.3390/medicina60010075

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OBJECTIVES: Although ChatGPT was not developed for medical use, there is growing interest in its use in medical fields. Understanding its capabilities and precautions for its use in the medical field is an urgent matter. We hypothesized that differences in the amounts of information published in different medical fields would be proportionate to the amounts of training ChatGPT receives in those fields, and hence its accuracy in providing answers. STUDY DESIGN: A non-clinical experimental study. METHODS: We administered the Japanese National Medical Examination to GPT-3.5 and GPT-4 to examine the rates of accuracy and consistency in their responses. We counted the total number of documents in the Web of Science Core Collection per medical field and assessed the relationship with ChatGPT's accuracy. We also performed multivariate-adjusted models to investigate the risk factors for incorrect answers. RESULTS: For GPT-4, we confirmed an accuracy rate of 81.0 % and a consistency rate of 88.8 % on the exam; both showed improvement compared to those for GPT-3.5. A positive correlation was observed between the accuracy rate and consistency rate (R = 0.51, P < 0.001). The number of documents per medical field was significantly correlated with the accuracy rate in that medical field (R = 0.44, P < 0.05), with relatively few publications being an independent risk factor for incorrect answers. CONCLUSIONS: Checking consistency may help identify incorrect answers when using ChatGPT. Users should be aware that the accuracy of the answers by ChatGPT may decrease when it is asked about topics with limited published information, such as new drugs and diseases.

DOI： 10.1016/j.ijmedinf.2023.105283

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGERNATURE  

Primary aldosteronism is the most frequent secondary hypertensive disease and is characterized by an elevated risk for cardiovascular disease. The current standard treatments are adrenalectomy and/or administration of mineralocorticoid receptor blockers, both of which are effective at ameliorating hypertension via intervention for hyperaldosteronism. However, both of these approaches have side effects and contraindications, and mineralocorticoid receptor blockers also have limited preventive efficacy against cardiovascular events. Recently, in vitro experiments have shown that aldosterone regulation is closely related to abdominal fat accumulation and that there is crosstalk between aldosterone and visceral fat tissue accumulation. We previously reported that this interaction was clinically significant in renal dysfunction; however, its effects on the heart remain unclear. Here, we analyzed data from 49 patients with primary aldosteronism and 29 patients with essential hypertension to examine the potential effect of the interaction between the ratio of visceral-to-subcutaneous fat tissue volume and the plasma aldosterone concentration on echocardiographic indices, including the tissue Doppler-derived E/e' ratio. A significant interaction was found in patients with primary aldosteronism (p < 0.05), indicating that patients with the combination of a high plasma aldosterone concentration and high visceral-to-subcutaneous fat ratio show an increased E/e' ratio, which is a well-known risk factor for future cardiovascular events. Our results confirm the clinical importance of the interaction between aldosterone and abdominal fat tissue, suggesting that an improvement in the visceral-to-subcutaneous fat ratio may be synergistically and complementarily effective in reducing the elevated risk of cardiovascular disease in patients with primary aldosteronism when combined with conventional therapies for reducing aldosterone activity.

DOI： 10.1038/s41440-023-01170-9

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Background Chronic kidney disease-mineral and bone disorder (CKD-MBD), nutritional status, and uremia management have been emphasized for bone management in hemodialysis patients. Nevertheless, valuable data on the importance of muscle mass in bone management are limited, including whether conventional management alone can prevent osteoporosis. Thus, the importance of muscle mass and strength, independent of the conventional management in osteoporosis prevention among hemodialysis patients, was evaluated. Methods Patients with a history of hemodialysis 6 months or longer were selected. We assessed the risk for osteoporosis associated with calf circumference or grip strength using multivariable adjustment for indices of CKD-MBD, nutrition, and dialysis adequacy. Moreover, the associations between bone mineral density (BMD), calf circumference, grip strength, and bone metabolic markers were also evaluated. Results A total of 136 patients were included. The odds ratios (95% confidence interval) for osteoporosis at the femoral neck were 1.25 (1.04-1.54, P < 0.05) and 1.08 (1.00-1.18, P < 0.05) per 1 cm shorter calf circumference or 1 kg weaker grip strength, respectively. Shorter calf circumference was significantly associated with a lower BMD at the femoral neck and lumbar spine (P < 0.001). Weaker grip strength was also associated with lower BMD at the femoral neck (P < 0.01). Calf circumference or grip strength was negatively correlated with bone metabolic marker values. Conclusion Shorter calf circumference or weaker grip strength was associated with osteoporosis risk and lower BMD among hemodialysis patients, independent of the conventional therapies.

DOI： 10.1007/s10157-022-02308-8

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10157-023-02342-0

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Other Link： https://link.springer.com/article/10.1007/s10157-023-02342-0/fulltext.html

Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

BackgroundAn arteriovenous fistula (AVF) is the most frequently used dialysis access for haemodialysis. However, it can cause volume loading for the heart and may induce circulatory failure when performed in patients with low cardiac function. This study aimed to characterise patients with low cardiac function when initiating dialysis and determine how cardiac function changes after the dialysis access surgery.MethodsWe conducted a retrospective observational study at two centres incorporating 356 patients with end-stage kidney disease who underwent echocardiography before the dialysis access surgery.ResultsAn AVF and a subcutaneously fixed superficial artery were selected in 70.4% and 23.5% of 81 patients with reduced/mildly reduced (< 50%) left ventricular ejection fraction (LVEF), respectively, and in 94.2% and 1.1% of 275 patients with preserved (>= 50%) LVEF (p < 0.001), respectively. Follow-up echocardiography was performed in 70.4% and 38.2% of patients with reduced/mildly reduced and preserved LVEF, respectively, which showed a significant increase in LVEF (41 +/- 9-44 +/- 12%, p = 0.038) in patients with reduced/mildly reduced LVEF. LVEF remained unchanged in 12 patients with reduced/mildly reduced LVEF who underwent subcutaneously fixed superficial artery (30 +/- 10-32 +/- 15%, p = 0.527). Patients with reduced/mildly reduced LVEF had lower survival rates after surgery than those with preserved LVEF (p = 0.021 for log-rank).ConclusionThe LVEF subcategory was associated with dialysis access selection. After the dialysis access surgery, LVEF was increased in patients with reduced/mildly reduced LVEF. These results may help select dialysis access for patients initiating dialysis.

DOI： 10.1007/s10157-023-02323-3

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DOI： 10.1016/j.ekir.2022.09.005

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BACKGROUND: The life prognosis of elderly patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies-associated vasculitis (MPO-AAV) has been improved by reducing the corticosteroid or cyclophosphamide dose to avoid opportunistic infection. However, many elderly MPO-AAV patients experience recurrence and renal death. An effective and safer maintenance treatment method is necessary to improve the renal prognosis of MPO-AAV. METHODS: Patients with MPO-AAV who reached complete or incomplete remission after induction therapy were prospectively and randomly divided into mizoribine (MZR; n = 25) and control (n = 28) groups. The primary endpoint was relapse of MPO-AAV. The patients' serum MZR concentration was measured before (C0) and 3 h after taking the MZR. The maximum drug concentration (Cmax) and the serum MZR concentration curves were determined using population pharmacokinetics parameters. We also assessed the relationship between the MZR concentrations and adverse events. The observation period was 12 months. RESULTS: Fifty-eight MPO-AAV patients from 16 hospitals in Japan were enrolled. Ten patients relapsed (MZR group, n = 6; control group, n = 4; a nonsignificant between-group difference). Changes in the serum MZR concentration could be estimated for 22 of the 25 MZR-treated patients: 2 of the 11 patients who reached a Cmax of 3 μg/mL relapsed, whereas 4 of the 11 patients who did not reach this Cmax relapsed. The treatment of one patient with C0 > 1 μg/mL was discontinued due to adverse events. No serious adverse events occurred. CONCLUSION: There was no significant difference in the recurrence rate of MPO-AAV between treatment with versus without MZR.

DOI： 10.1007/s10157-022-02253-6

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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is shown to prevent severe illness and death in hemodialysis (HD) patients, but the immune response to vaccines is reduced in this population. This study compared SARS-CoV-2 spike protein antibody titers between HD patients and healthy controls in Japan for up to 6 months following vaccination. METHODS: A multi-institutional retrospective study at five clinics in Japan was conducted using 412 HD patients and 156 healthy controls who received two doses of the BNT162b2 (Pfizer-BioNTech) mRNA vaccine. Anti-SARS-CoV-2 spike protein S1 IgG antibody titers were measured at 1, 3, and 6 months after the second dose. The attenuation speed was calculated as slope (i.e., -β) using a linear mixed-effects model toward the log-transformed antibody titers. RESULTS: The HD group had significantly lower month 1 antibody titers (Ab-titer-1) than the controls, and these remained lower through month 6 (95% CI: 2617.1 (1296.7, 5240.8) vs. 7285.4 (4403.9, 11,000.0) AU/mL at Ab-titer-1, and 353.4 (178.4, 656.3) vs. 812.0 (498.3, 1342.7) AU/mL at Ab-titer-6 (p < 0.001, respectively)). Lower log Ab-titer-1 levels in the HD group were significantly associated with a lower log Ab-titer-6 (0.90 [0.83, 0.97], p < 0.001). The -β values in the HD patients and healthy controls were -4.7 ± 1.1 and -4.7 ± 1.4 (year-1), respectively. CONCLUSION: SARS-CoV-2 spike protein antibody titers were significantly lower in HD patients than in healthy controls at 1 (peak) and 6 months after the second vaccination. Low peak antibody titers contributed to low 6-month antibody titers.

DOI： 10.1007/s10157-022-02243-8

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Tolvaptan (TLV) is reported to improve diuretic effects in patients with chronic kidney disease (CKD) when furosemide (FUR) is not sufficiently effective. However, it is not clear whether TLV addition is effective for advanced CKD patients with heart failure. METHODS: An open-label, parallel-group randomized trial was performed. The subjects were 33 patients with CKD stage G3-G5 who had fluid overload despite taking 20-100 mg/day FUR. They were divided into two groups: a group administered 15 mg/day TLV plus their original FUR dose for 7 days (TLV group), and a group administered 120-200 mg/day FUR (i.e., 100 mg/day over their previous dose) for 7 days (FUR group). RESULTS: The mean change in urine volume was significantly higher in the TLV group compared to the FUR group (637 ml vs 119 ml; p < 0.05). The difference was greater when the urine osmolality before treatment was high. Serum creatinine was increased only in the FUR group. The incidence of worsening renal function (WRF) was significantly lower in the TLV group (18.8% vs 58.8%; p < 0.05). Serum sodium decreased significantly in the FUR group, but did not change in the TLV group. CONCLUSIONS: In patients with advanced CKD with fluid overload, the addition of TLV achieved a significantly higher urine volume with less adverse effects on renal function compared with increasing the dose of FUR. The efficacy and safety of TLV were higher in patients who had higher urine osmolality and lower serum sodium before treatment. CLINICAL TRIAL REGISTRATION: UMIN000014763.

DOI： 10.1007/s10157-022-02224-x

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BACKGROUND: We previously showed Lipin1 (LPIN1) to be a candidate gene for essential hypertension by genome-wide association studies. LPIN1 encodes the Lipin 1 protein, which contributes to the maintenance of lipid metabolism and glucose homeostasis. However, little is known about the association between LPIN1 and blood pressure (BP). METHODS: We evaluated the BP of LPIN1-deficient [fatty liver dystrophy (fld)] mice and explored related mechanisms. RESULTS: Fld mice have very low expression of LPIN1 and exhibit fatty liver, hypertriglyceridemia, insulin resistance and peripheral neuropathy. Fld mice had significantly elevated SBP and heart rate (HR) throughout the day as measured by a radiotelemetric method. Diurnal variation of SBP and HR was also absent in fld mice. Furthermore, urinary excretion of adrenaline and noradrenaline by fld mice was significantly higher compared with that of control mice. The BP response of fld mice to clonidine (a centrally acting α2-adrenergic receptor agonist) was greater than that of control mice. However, levels of Angiotensinogen and Renin 1 mRNA and urinary nitric oxide excretion were comparable between the two groups. The decrease in SBP at 8 weeks after fat grafting surgery was significantly greater in the transplant group compared with the sham operated group. CONCLUSION: The elevated BP in fld mice may result from activation of the sympathetic nervous system through decreased levels of adipose cytokines. These results indicate that LPIN1 plays a crucial role in blood pressure regulation and that LPIN1 is a new target gene for essential hypertension.

DOI： 10.1097/HJH.0000000000003046

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(一社)日本小児腎臓病学会  

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Language：Japanese   Publisher：(一社)日本小児腎臓病学会  

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Patients with primary aldosteronism have a higher risk of chronic kidney disease. Visceral fat tissue is hypothesized to stimulate the adrenal glands to overproduce aldosterone, and aldosterone promotes visceral fat tissue to produce inflammatory cytokines. However, it is unclear whether the volume of accumulated visceral fat tissue is associated with renal impairment among patients with hyperaldosteronism. We conducted a single-center cross-sectional study to assess the association between the estimated glomerular filtration rate and the ratio of the visceral-to-subcutaneous fat volume calculated by computed tomography. One hundred eighty patients with primary aldosteronism were enrolled. The mean ± SD age was 52.7 ± 11.0 years, and 60.0% were women. The ratio of visceral-to-subcutaneous fat volume was highly correlated with the estimated glomerular filtration rate (r = 0.49, p < 0.001). In multiple linear regression models, the ratio of visceral-to-subcutaneous fat tissue volume was significantly associated with the estimated glomerular filtration rate (estimates: -4.56 mL/min/1.73 m² per 1-SD), and there was an interaction effect between the plasma aldosterone concentration and the ratio of visceral-to-subcutaneous fat volume (p < 0.05). The group with a higher plasma aldosterone concentration exhibited a steeper decline in eGFR than the lower plasma aldosterone concentration group when the ratio increased. The ratio of visceral-to-subcutaneous fat tissue volume was an independent risk factor for renal dysfunction. This association increased in the presence of a high plasma aldosterone concentration. Clinicians should pay attention to the ratio of visceral-to-subcutaneous fat tissue volume and encourage primary aldosteronism patients to improve their lifestyle in addition to treating renin-aldosterone activity.

DOI： 10.1038/s41440-021-00719-w

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BACKGROUND: Diabetic kidney disease (DKD) is one of the main complications of type 2 diabetes mellitus (T2DM). DKD is a known risk factor for end-stage renal disease, cardiovascular disease, and all-cause death. Effective intervention for early-stage DKD is vital to slowing down the progression of kidney disease and improve prognoses. Mobile health (mHealth) is reportedly effective in supporting patients' self-care and improving glycemic control, but the impact of mHealth on DKD has yet to be shown. OBJECTIVE: The purpose of this study is to evaluate the efficacy of standard therapy with the addition of a self-management support system, DialBetesPlus, in patients with DKD and microalbuminuria. METHODS: This study is a prospective, randomized, open-label, multicenter clinical trial. The target population consists of 160 patients diagnosed with T2DM accompanied by microalbuminuria. We randomly assigned the patients to 2 groups-the intervention group using DialBetesPlus in addition to conventional therapy and the control group using conventional therapy alone. DialBetesPlus is a smartphone application that supports patients' self-management of T2DM. The study period was 12 months, with a follow-up survey at 18 months. The primary outcome was a change in albuminuria levels at 12 months. Secondary outcomes included changes in physical parameters, blood test results (glycemic control, renal function, and lipid metabolism), lifestyle habits, self-management scores, medication therapy, and quality of life. RESULTS: The study was approved in April 2018. We began recruiting patients in July 2018 and completed recruiting in August 2019. The final 18-month follow-up was conducted in March 2021. We recruited 159 patients and randomly allocated 70 into the intervention group and 61 into the control group, with 28 exclusions due to withdrawal of consent, refusal to continue, or ineligibility. The first results are expected to be available in 2021. CONCLUSIONS: This is the first randomized controlled trial assessing the efficacy of mHealth on early-stage DKD. We expect that albuminuria levels will decrease significantly in the intervention group due to improved glycemic control with ameliorated self-care behaviors. TRIAL REGISTRATION: UMIN-CTR UMIN000033261; https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000037924. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31061.

DOI： 10.2196/31061

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: We used a dataset from a Japanese nationwide registry of patients with primary aldosteronism, to determine which of the parameters of hyperaldosteronism and blood pressure before or after treatments for primary aldosteronism (i.e., surgical adrenalectomy or a medication treatment) are important in terms of cardiovascular prognosis. METHODS: We assessed whether plasma aldosterone-to-renin ratio and pulse pressure levels before treatment and 6 months after treatment were associated with composite cardiovascular disease events during the 5-year follow-up period. RESULTS: The cohort included 1987 patients (mean age was 53.2 years, 52.0% were female, 37.2% had undergone surgical treatment, and the remainder had been treated with mineralocorticoid receptor antagonists). In the Cox proportional hazard model, the covariate-adjusted hazard ratio (95% confidence interval) for the composite cardiovascular disease events risk for each one-standard-deviation increase in the aldosterone-to-renin ratio or pulse pressure before treatment, those after treatment, or the duration of hypertension were 1.24 (1.05, 1.48), 0.74 (0.54, 1.02), and 1.07 (0.79, 1.44), 1.43 (1.07, 1.92), and 1.52 (1.19, 1.95), respectively. Patients with a high pre-treatment aldosterone-to-renin ratio of more than 603 and a large post-treatment pulse pressure of more than 49 mmHg showed approximately three-fold higher hazard ratios for cardiovascular events risk compared to those with a lower aldosterone-to-renin ratio and smaller pulse pressure. CONCLUSIONS: Higher aldosterone-to-renin ratio before treatments, higher pulse pressure after treatments, and longer duration of hypertension were prognostic factors for cardiovascular diseases. Early intervention may be important for preventing cardiovascular disease among patients with primary aldosteronism.

DOI： 10.1016/j.atherosclerosis.2021.03.033

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

Background It is not elucidated that there is treatment-related damage in elderly patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods Elderly (>= 75 years of age) patients were enrolled from two nationwide prospective inception cohort studies. The primary outcome was 12-month treatment-related Vasculitis Damage Index (VDI) score. Secondary outcomes included serious infections within 6 months, total VDI score, remission, and relapse. Patient characteristics and outcomes were compared across three different initial glucocorticoid (GC) dose groups: high-dose, prednisolone (PSL) >= 0.8 mg/kg/day; medium-dose, 0.6 <= PSL < 0.8 mg/kg/day; and low-dose, PSL < 0.6 mg/kg/day. Results Of the 179 eligible patients, the mean age was 80.0 years; 111 (62%) were female. The mean Birmingham Vasculitis Activity Score was 16.1. Myeloperoxidase-ANCA findings were positive in 168 (94%) patients, while proteinase 3-ANCA findings were positive in 11 (6%). The low-dose group was older and had higher serum creatinine levels than the other groups. There were no statistically significant intergroup differences in remission or relapse, whereas serious infection developed more frequently in the high-dose (29 patients [43%]) than the low-dose (13 patients [22%]) or medium-dose (10 patients [19%]) groups (p = 0.0007). Frequent VDI items at 12 months included hypertension (19%), diabetes (13%), atrophy and weakness (13%), osteoporosis (8%), and cataracts (8%). Logistic regression analysis revealed that GC dose at 12 months (odds ratio, 1.14; 95% confidence interval, 1.00-1.35) was a predictor for diabetes. Conclusion A reduced initial GC dose with rapid reduction might be required to ensure the safe treatment of elderly AAV patients.

DOI： 10.1186/s13075-020-02341-6

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41440-019-0284-9

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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BACKGROUND: The prognostic value of the EUVAS-proposed histopathological classification of anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis has been evaluated throughout the world. Here, we performed a Japanese nationwide biopsy survey to assess the association between this histopathological classification and renal prognosis after 2-year follow-up in ANCA-associated glomerulonephritis. METHODS: We collected 67 renal biopsy materials of the 321 entries in the RemIT-JAV-RPGN cohort study, and assessed their histologies. Based on the EUVAS-proposed histopathological classification and some histological parameters, we statistically evaluated renal survival and the comparison of renal function for 2 years. RESULTS: Based on the histopathological classification, the largest number of biopsy samples belonged to the Focal class, followed by the Mixed, Crescentic, and Sclerotic classes (n = 30, 19, 10, 8, respectively). Although the number of events might be too low (four patients with renal death) to make this conclusion, the Focal and Mixed classes had higher renal-survival rates compared to the others in the renal-survival curve. Comparing renal function among all classes, the estimated glomerular filtration rate (eGFR) throughout 2-year follow-up period was significantly higher in the Focal class compared to the other 3 classes. The eGFR-values in the Crescentic, Mixed, and Sclerotic classes increased with time. Based on both combined results, the Focal class could be the best prognosis. CONCLUSION: This histopathological classification was valuable for both the stratification of renal function and the estimation of partial renal survival during 2-year follow-up in ANCA-associated glomerulonephritis.

DOI： 10.1007/s10157-018-1656-1

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：日本ベーリンガーインゲルハイム(株)  

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DOI： 10.1097/01.hjh.0000549026.56437.42

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DOI： 10.1097/01.hjh.0000548693.27681.44

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DOI： 10.1097/01.hjh.0000548931.92288.07

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Oxidative stress accelerates the development of cardiovascular disease. Plasma cystine, a thiol oxidative stress marker, is related to several established factors for cardiovascular disease risk and prognosis. Although a comprehensive oxidative stress index is clinically required for hemodialysis patients with high oxidative stress, there are few reports concerning thiol oxidative stress markers predicting their prognosis. We investigated the relationship between plasma amino acids including cystine levels and cardiovascular disease-related and all-cause mortality in 132 maintenance hemodialysis patients. Higher cystine levels were associated with old age, longer hemodialysis duration, hemodialysis-associated hypotension, higher cardiothoracic ratio, higher blood urea nitrogen, and lower ankle-brachial index. Multivariate Cox regression analysis revealed that high plasma cystine was independently related with both cardiovascular disease mortality and all-cause mortality. Thus, high plasma cystine levels predict the prognosis of hemodialysis patients. High cystine levels necessitate a careful investigation for the cause of oxidative stress and comorbidities like vascular injury.

DOI： 10.1111/1744-9987.12669

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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BACKGROUND: Arterial hypertrophy and interstitial fibrosis are important characteristics in kidneys of angiotensinogen-knockout (Atg -/-) mice. In these mice, which exhibit polyuria and hypotension, sympathetic nerve signaling is estimated to be compensatorily hyperactive. Furthermore, transforming growth factor (TGF)-β1 is overexpressed in mice kidneys. To determine whether sympathetic nerve signaling and TGF-β1 exacerbate arterial hypertrophy and interstitial fibrosis, intervention studies of such signaling are required. METHODS: We performed renal denervation and administered the α2-adrenergic receptor (AR) antagonist, atipamezole, to Atg -/- mice. A renin inhibitor, aliskiren, which was preliminarily confirmed to reduce TGF-β1 gene expression in kidneys of the mice, was additionally administered to assess the effect on the arterial hypertrophy and interstitial fibrosis. RESULTS: Norepinephrine content in kidneys of Atg -/- mice was three times higher than in kidneys of wild-type mice. Interventions by renal denervation and atipamezole resulted in amelioration of the histological findings. Overexpression of TGF-β1 gene in kidneys of Atg -/- mice was altered in a manner linked to the histological findings. Surprisingly, aliskiren reduced α2-AR gene expression, interstitial fibrosis, and arterial hypertrophy in kidneys of Atg -/- mice, which lack renin substrate. CONCLUSIONS: Alpha2-AR signaling is one of the causes of persistent renal arterial hypertrophy in Atg -/- mice. Aliskiren also angiotensinogen-independently reduces the extent of renal arterial hypertrophy, partly thorough downregulation of α2-ARs. Although renal arterial hypertrophy in Atg -/- mice appears to be of multifactorial origin, TGF-β1 may play a key role in the persistence of such hypertrophy.

DOI： 10.1007/s10157-017-1520-8

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

The ATP2B1 gene is associated with hypertension. We previously reported that systemic heterozygous ATP2B1-null (ATP2B1+/−) mice exhibited hypertension due to impaired endothelial nitric oxide synthase (eNOS) activity and decreased nitric oxide (NO) production. The ATP2B1 gene encodes plasma membrane calcium ATPase 1 (PMCA1), which has been thought to regulate only intracellular Ca2+ concentration. However, recently, it has been suggested that ATP2B1 works not only at cellular levels, but also throughout the entire body, including in the calcium metabolism, using small intestine-specific ATP2B1 knockout mice. To clarify the roles of ATP2B1 in the entire body and the effects of ATP2B1 on blood pressure, we examined the alterations of calcium related factors in ATP2B1+/− mice. ATP2B1+/− mice exhibited hypocalcemia. The expression of ATP2B1 in the kidney and small intestine decreased, and hypercalciuria was confirmed in ATP2B1+/− mice. The intact-PTH levels were lower, and bone mineral density was increased in these mice. These results suggest that hypocalcemia is mainly a result of inhibited bone resorption without compensation by PTH secretion in the case of ATP2B1 knockout. Moreover, NO production may be affected by reduced PTH secretion, which may cause the increase in vascular contractility in these mice. The ATP2B1 gene is important for not only intra-cellular calcium regulation but also for calcium homeostasis and blood pressure control.

DOI： 10.1038/s41440-018-0067-8

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The carotid bulb has a high density of baroreceptors that play an important role in maintaining blood pressure. We hypothesized that atherosclerosis of the carotid bulb would reflect the severity of orthostatic hypotension more accurately than would atherosclerosis of other carotid artery segments. METHODS: This cross-sectional study included 198 non-diabetic adults. We measured the cardio-vascular ankle index as an index of arterial stiffness, intima-media thickness in each carotid artery segment (internal carotid artery, carotid bulb, distal and proximal portions, respectively, of the common carotid artery) as a measure of atherosclerosis, and heart rate variability as a measure of cardiac autonomic function. The sit-to-stand test was used to assess severity of orthostatic hypotension. RESULTS: Intima-media thickness of the carotid bulb was correlated with orthostatic systolic blood pressure change (r = -0.218, p = 0.002), cardio-ankle vascular index (r = 0.365, p < 0.001) and heart rate variability parameters. Multivariate regression analysis revealed that among all of the segments, only intima-media thickness of the carotid bulb was an independent predictor of orthostatic systolic blood pressure change (p = 0.022). CONCLUSION: Atherosclerosis of the carotid bulb was associated with severity of orthostatic hypotension, arterial stiffening and cardiac autonomic dysfunction than that of other carotid artery segments.

DOI： 10.1080/10641963.2018.1465073

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

ATP2B1 is a gene associated with hypertension. We reported previously that mice lacking ATP2B1 in vascular smooth muscle cells (VSMC ATP2B1 KO mice) exhibited high blood pressure and increased intracellular calcium concentration. The present study was designed to investigate whether lack of the ATP2B1 gene causes a higher response to calcium channel blockers (CCBs) than to other types of anti-hypertensive drugs. Both VSMC ATP2B1 KO and control mice were administered anti-hypertensive drugs while monitoring blood pressure shifts. We also examined the association of nitric oxide synthase (NOS) activity in those mice to investigate whether another mechanism of hypertension existed. VSMC ATP2B1 KO mice exhibited significantly greater anti-hypertensive effects with a single injection of nicardipine, but the effects of an angiotensin II receptor blocker (ARB), an α-blocker and amlodipine on blood pressure were all similar to control mice. However, long-term treatment with amlodipine, but not an ARB, significantly decreased the blood pressure of KO mice compared with control mice. Both mRNA and protein expression levels of the L-type calcium channel were significantly upregulated in KO VSMCs. There were no alterations in neural NOS protein expression of VSMCs or in urinary NO production between the two groups. VSMC ATP2B1 KO mice had a higher response to CCBs for blood pressure-lowering effects than other anti-hypertensive drugs. These results mean that increased intracellular calcium concentration in VSMCs due to lack of ATP2B1 and subsequent activation of L-type calcium channels mainly affects blood pressure and suggests increased susceptibility to CCBs in this type of hypertension.

DOI： 10.1038/hr.2017.92

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/jhh.2017.53

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Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/jhh.2017.41

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Tolvaptan, a vasopressin V-2 receptor blocker, has a diuretic effect for patients with heart failure. However, there were a few data concerning the effects of tolvaptan in patients with chronic kidney disease (CKD).
We retrospectively analyzed 21 patients with chronic heart failure and CKD. Tolvaptan was co-administered with other diuretics in-use, every day. We compared clinical parameters before and after the treatments with tolvaptan. Furthermore, we examined the correlations between baseline data and the change of body weight.
Tolvaptan decreased the body weight and increased the urine volume (p = 0.001). The urine osmolality significantly decreased throughout the study period. Urinary Na/Cr ratio and FENa changed significantly after 4 h, and more remarkable after 8 h (p = 0.003, both). Serum creatinine increased slightly after 1 week of treatment (p = 0.012). The alteration of body weight within the study period correlated negatively with the baseline urine osmolality (r = -0.479, p = 0.038), the baseline urine volume (r = -0.48, p = 0.028), and the baseline inferior vena cava diameter (IVCD) (r = -0.622, p = 0.017). Hyponatremia was improved to the normal value, and the augmentations of the sodium concentration were negatively associated with the basal sodium levels (p = 0.01, r = -0.546).
Tolvaptan is effective in increasing diuresis and improved hyponatremia, even in patients with CKD. The baseline urine osmolality, urine volume, and IVCD may be useful predictors for diuretic effects of tolvaptan.

DOI： 10.1007/s10157-016-1379-0

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Plasma membrane calcium pump isoform 1 (PMCA1) is encoded by ATPase plasma membrane Ca
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transporting 1 (ATP2B1), the most likely candidate gene responsible for hypertension. Although PMCA1 is highly expressed in the kidney, little is known about regulation of its renal expression in various pathological conditions in vivo. Our study was designed to elucidate regulation of renal PMCA1 expression in mice. We employed three mouse models for kidney disease. These were the unilateral ureteral obstruction (UUO), the remnant kidney using 5/6 nephrectomy, and chronic angiotensin II administration models. Mice were assessed for systolic blood pressure and renal injury in accordance with the damage induced in the specific model. Kidney PMCA1 mRNA levels were measured in all mice. The UUO model showed renal fibrosis but no changes in blood pressure or renal PMCA1 mRNA expression. Similarly, the 5/6 nephrectomy model exhibited declined renal function without changes in blood pressure or renal PMCA1 mRNA expression. In contrast, chronic angiotensin II administration increased albuminuria and blood pressure as well as significantly increasing renal PMCA1 mRNA and protein expression. These results suggest that renal PMCA1 has a role as one of the molecules involved in angiotensin II-induced hypertension and kidney injury.

DOI： 10.14814/phy2.13316

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s41100-017-0103-1

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ATHEROSCLEROSIS SOC  

Aim: Patients with orthostatic hypotension (OH) have high arterial stiffness. Patients with diabetes mellitus (DM) often have cardiac autonomic neuropathy that leads to OH; however, whether OH is an indicator of arterial stiffness progression is unclear. We aimed to investigate whether the cardioankle vascular index (CAVI) varies between DM patients with and without OH using the sit-to-stand test (STST).
Methods: One hundred and fifty-nine patients with DM underwent CAVI assessment and blood pressure (BP) and heart rate change evaluation during the STST. OH was defined as a decline in systolic BP (SBP) and/or diastolic BP of at least 20 mmHg or 10 mmHg, respectively, in the initial and late upright positions compared with that in the sitting position.
Results: OH was diagnosed in 42 patients (26.4%). DM patients with OH had significantly higher CAVI (9.36 +/- 1.15 versus 8.89 +/- 1.18, p= 0.026) than those without OH. CAVI was significantly inversely correlated with systolic and diastolic BP changes (R =-0.347, p &lt; 0.001 and R=-0.314, p &lt; 0.001, respectively) in the initial upright position. Multivariate regression analysis revealed that age, SBP changes, and low frequency component in the initial upright position were independent determinants of CAVI.
Conclusion: Patients with DM having large BP drops occurring when moving from sitting to standing have high arterial stiffness. A significant BP drop during the STST necessitates careful evaluation of advanced arterial stiffness in patient with DM.

DOI： 10.5551/jat.34645

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Few studies have examined how renin-angiotensin system inhibitors (RASI) delay dialysis initiation in patients with advanced chronic kidney disease (CKD). We conducted a retrospective survey to examine this subject.
We reviewed the records of patients with advanced CKD for the 60-month period before dialysis initiation between 1990 and 2015. Patients were classified based on the decade of dialysis initiation into the 1990s, 2000s, and 2010s groups. The rates of antihypertensive medications administered were assessed. The rate of decline of renal function was evaluated by the slope of reciprocal serum creatinine (SRSC). Multiple regression analyses were conducted to evaluate factors contributing to renoprotection.
The duration of RASI administration was longer in the 2010s than in 2000s and 1990s. Both diabetic and non-diabetic patients had lower SRSC in the 2010s compared to the 2000s. In the 2010s, the rate of RASI administration during the 60-month pre-dialysis period showed an initial rise followed by a downward trend, although the rates of administration of the other classes of antihypertensives increased continuously. Multivariate regression analyses identified age, blood pressure, diuretics, alpha-blockers, alpha-methyldopa and RASI as independent predictors of SRSC in the 2010s. The rate of RASI administration correlated with serum potassium concentration.
Our findings suggest that in the 2010s, RASI with other antihypertensive agents contributed to renoprotection in advanced CKD patients, but they were underused because of the concern over hyperkalemia. In real-world clinical practice, physicians may feel great hesitation in using RASI in patients with advanced CKD.

DOI： 10.1007/s10157-015-1191-2

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DOI： 10.1093/ndt/gfw174.03

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

It remains unclear whether the abnormal circadian blood pressure (BP) rhythm in non-diabetic chronic kidney disease (CKD) is related to hypoalbuminemia. We evaluated relationships between circadian BP rhythm and serum albumin concentration (SAC) and also examined autonomic nervous activities. Non-diabetic CKD patients with proteinuria (n=197; 105 men, 92 women; aged 47.0 +/- 13.3 years; estimated glomerular filtration rate30 ml/min) were divided into nephrotic syndrome (NS: n=46, SAC30 g/l), hypoalbuminemia (n=65, 30&lt;SAC&lt;40 g/l) and normoalbuminemia (n=86, SAC40 g/l) groups. Non-proteinuria subjects (n=97, urinary protein/creatinine ratio&lt;30mg/g creatinine) were enrolled as the non-proteinuria group. Ambulatory 24 h BP monitoring was conducted in all subjects. Simultaneously, power spectral analysis of heart rate was performed to evaluate the sympathovagal balance. Waking BP was lower in the hypoalbuminemia and NS groups than the other groups. Sleeping/waking mean BP ratio was not different between non-proteinuria (0.87 +/- 0.07) and normoalbuminemia (0.89 +/- 0.08) groups, but increased significantly (p&lt;0.05) in the hypoalbuminemia (0.92 +/- 0.08) and NS groups (0.96 +/- 0.08). Significant reverse correlations were observed between SAC and sleeping/waking mean BP ratio (r=-0.274, p&lt;0.001) in all patients. Multivariate regression analysis identified SAC and sympathovagal balance as predictors of increased sleeping/waking BP ratios as the dependent variable. In non-diabetic CKD patients with proteinuria, disturbed circadian BP rhythms were related to SAC and 24 h sympathovagal imbalance.

DOI： 10.3109/08037051.2016.1095916

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis in many parts of the world. Although previous genome-wide association studies (GWAS) identified the major susceptibility loci for IgAN, the causal genes currently remain unknown. We performed a GWAS using 23 465 microsatellite (MS) markers to identify genes related to IgAN in a Japanese population. A pooled sample analysis was conducted in three-stage screenings of three independent case-control populations, and after the final step of individual typing, 11 markers survived. Of these, we focused on two regions on 6p21 and 12q21 because they (i) showed the strongest relationship with IgAN, and (ii) appeared to be highly relevant to IgAN in view of several previous studies. These regions contained the HLA, TSPAN8 and PTPRR genes. This study on GWAS, using &gt;20 000 MS markers, provides a new approach regarding susceptible genes for IgAN for investigators seeking new tools for the prevention and treatment of IgAN.

DOI： 10.1038/jhg.2015.88

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Cyclosporine and prednisolone combination therapy has been used in the treatment of minimal change nephrotic syndrome (MCNS). However, few studies have evaluated the efficacy of cyclosporine combined with intravenous methylprednisolone pulse therapy (MPT) as a first-line treatment for new-onset MCNS. We conducted a retrospective clinical study to evaluate the efficacy and safety of cyclosporine combined with MPT and oral prednisolone for new-onset MCNS in adults.
Forty-six adult patients with biopsy-proven MCNS were analyzed retrospectively. This study included three groups. Group 1 (n = 17) was treated with intravenous MPT (0.5 or 1.0 g/day for 3 days) followed by oral cyclosporine (2-3 mg/kg/day) and prednisolone (30 mg/day). Group 2 (n = 15) was treated with intravenous MPT followed by oral prednisolone (0.4-0.8 mg/kg/day). Group 3 (n = 14) was treated with oral prednisolone (0.6-1.0 mg/kg/day) alone.
The length of hospital stay was the shortest in Group 1 (P &lt; 0.001). The mean duration to achieve &lt; 20 mg/day of prednisolone was also the shortest in Group 1 (P &lt; 0.05). Complete remission rates were 100 % in Group 1, 85.7 % in Group 2, and 69.2 % in Group 3 during the 9-month follow-up (P = 0.073). The rate of adverse effects caused by prednisolone was less in Group 1 (P &lt; 0.05). Multivariate analysis revealed that the independent determinants of durations of remission were the selectivity index (P = 0.004), eGFR (P = 0.001) and the use of cyclosporine (P = 0.045).
Combination therapy with cyclosporine may be a beneficial treatment option for new-onset MCNS in adults because of its clinical efficacy and safety.

DOI： 10.1007/s10157-014-0975-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

This study aimed to evaluate the effect of different timings of iron administration during erythropoiesis activated by continuous erythropoietin receptor activator (CERA) on reticulocyte iron uptake in hemodialysis patients. In total, 110 patients were randomized to receive 40mg intravenous elemental iron doses at all three hemodialysis sessions in the first week (IW1 group: n = 57) or in the third week (IW3 group: n = 53) after CERA administration. Following CERA administration at day 0, reticulocyte count increased, peaking at day 7. At days 7 and 14, the observed changes in Ret-He were higher in the IW1 group than in the IW3 group. Increases in total reticulocyte hemoglobin at day 7 were higher in the IW1 group than in the IW3 group. In contrast, there was only tendency toward greater total reticulocyte hemoglobin after iron administration in the third week in the IW3 group. Intravenous iron supplementation in the first week of CERA administration increases reticulocyte iron uptake; however, iron supplementation in the third week does not. The findings indicate that iron should be intravenously administered to increase the efficacy of CERA within 1 week of CERA administration during highly active erythropoiesis.

DOI： 10.1111/1744-9987.12237

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

We conducted a prospective study to assess the effects of doxazosin, as the third agent, on morning and position-related blood pressure (BP) in 77 diabetic patients with chronic kidney disease, who were allocated randomly to doxazosin and diuretics groups. Doxazosin decreased morning BP but diuretics could not decrease pre-awakening diastolic BP. Only doxazosin improved sympathovagal balance. Doxazosin and diuretics decreased standing and sitting BP but only doxazosin improved sympathovagal balance regardless of body positions. Doxazosin did not decrease absolute BP changes shortly after standing. In diabetic patients, doxazosin decreased morning BP through improving sympathovagal balance without causing significant orthostatic hypotension (ClinicalTrials.gov number, NCT00295555).

DOI： 10.3109/10641963.2014.913599

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During hemodialysis, amino acid loss through the dialysate remained a significant problem and was not clear in some dialyzers; therefore, we investigated amino acid loss with hydrophilic and nonhydrophilic polyester-polymer alloy membranes and polyacrylonitrile membranes. Nine maintenance hemodialysis patients were studied to assess amino acid loss during hemodialysis with the three membranes. Total amino acid losses were 85.7 +/- 27.2 mg/L, 83.3 +/- 16.1 mg/L, and 72.1 +/- 22.5 mg/L with the hydrophilic, nonhydrophilic polyester-polymer alloy, and polyacrylonitrile membranes, respectively. Amino acid losses were greater with the hydrophilic membrane compared with the polyacrylonitrile membrane for ornithine (2.0 +/- 0.6 vs. 1.4 +/- 0.4 mg/L, P = 0.025), phenylalanine (2.4 +/- 0.9 vs. 1.8 +/- 0.8 mg/L, P = 0.012), and tryptophan (0.6 +/- 0.2 vs. 0.4 +/- 0.2 mg/L, P = 0.023). Amino acid losses were greater with the nonhydrophilic membrane than with the polyacrylonitrile membrane for ornithine (2.0 +/- 0.4 vs. 1.4 +/- 0.4 mg/L, P = 0.017), phenylalanine (2.3 +/- 0.5 vs. 1.8 +/- 0.8 mg/L, P = 0.018), tryptophan (0.7 +/- 0.2 vs. 0.4 +/- 0.2 mg/L, P = 0.003), and cystine (3.2 +/- 0.7 vs. 2.0 +/- 0.7 mg/L, P = 0.005). In conclusion, greater losses of ornithine, phenylalanine, tryptophan, and cystine were observed with polyester-polymer alloy than with polyacrylonitrile membranes during hemodialysis. Constant attention should be paid to the amino acid loss profile to improve nutritional control in hemodialysis patients.

DOI： 10.1111/1744-9987.12145

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background: In the `Millennium Genome Project', we identified ATP2B1 as a gene responsible for hypertension through single-nucleotide polymorphism analysis. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which contributes to the maintenance of intracellular calcium homeostasis by removing calcium ions.
Method: Since ATP2B1 knockout mice are reported to be embryo-lethal, we generated systemic heterozygous ATP2B1 null (ATP2B1(+/-)) mice, and evaluated the implication of ATP2B1 in blood pressure.
Results: ATP2B1(+/-) mice revealed significantly higher SBP as measured by a radiotelemetric method. Phenylephrine-induced vasoconstriction was significantly increased in vascular rings from ATP2B1(+/-) mice, and the difference in this contraction disappeared in the presence of a nitric oxide synthase (NOS) inhibitor. Vasorelaxation to acetylcholine was significantly attenuated in vascular rings from ATP2B1(+/-) mice. In addition, cultured endothelial cells of ATP2B1(+/-) mice showed that the phosphorylation (Ser-1177) level of endothelial NOS protein was significantly lower, and nitric oxide production in endothelial cells and aorta was lower compared with those in control mice. In contrast, neural NOS expression in vascular smooth muscle cells from ATP2B1(+/-) mice and control mice were not significantly different.
Conclusion: These results suggest that decreased ATP2B1 gene expression is associated with impaired endothelial NOS activity and nitric oxide production, and the ATP2B1 gene plays a crucial role in the regulation of blood pressure.

DOI： 10.1097/HJH.0000000000000206

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Language：Japanese   Publisher：(一社)日本透析医学会  

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&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt;&lt;i&gt;TSPAN8&lt;/i&gt; encoding tetraspanin-8 was identified as a candidate gene for immunoglobulin A nephropathy (IgAN) by a genome-wide association study using microsatellites in the Japanese population. Tetraspanin-8 is a cell surface protein that contributes to the migration and invasion of epithelial cells. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We performed immunohistochemistry for tetraspanin-8 on human renal biopsy specimens associated with IgAN, antineutrophil cytoplasmic antibody-associated nephropathy and interstitial nephritis, as well as normal renal tissue. Furthermore, to study the potential function of tetraspanin-8, we performed cell migration and invasion assays using human renal tubule cells transfected with tetraspanin-8. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Tetraspanin-8 was often expressed in vascular smooth muscle cells and occasionally in tubule cells in normal kidney. In the kidneys of all types of nephropathy, tetraspanin-8 staining in the arteries was unaffected, but that in the tubules was enhanced. The degree of tubular staining negatively correlated with the estimated glomerular filtration rate, independently of the type of nephropathy. Tetraspanin-8-expressing tubule cells were found predominantly in distal and collecting tubules, identified by cytokeratin 7 or aquaporin 2 staining. In vitro studies using cultured tubule cells revealed that tetraspanin-8 promoted migration by 2.7-fold without laminin, by 2.8-fold with laminin and invasion into Matrigel by 3.5-fold, suggesting that enhanced tetraspanin-8 may be involved in the repair of tubules. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; The obtained findings indicate that tetraspanin-8 expression is enhanced in injured distal tubules, which may be involved in the repair of tubules by facilitating migration and invasion.

DOI： 10.1159/000362451

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background-Metabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life-threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause of visceral obesity-related metabolic disorders, moving the tissue toward a proinflammatory phenotype.
Methods and Results-Here we first report that adipose tissues from patients and mice with metabolic disorders exhibit decreased expression of ATRAP/Agtrap, which is a specific binding modulator of the angiotensin II type 1 receptor, despite its abundant expression in adipose tissues from normal human and control mice. Subsequently, to examine a functional role of ATRAP in the pathophysiology of metabolic disorders, we produced homozygous ATRAP deficient (Agtrap(-/-)) mice, which exhibited largely normal physiological phenotype at baseline. Under dietary high fat loading, Agtrap(-/-) mice displayed systemic metabolic dysfunction, characterized by an increased accumulation of pad fat, hypertension, dyslipidemia, and insulin resistance, along with adipose tissue inflammation. Conversely, subcutaneous transplantation of donor fat pads overexpressing ATRAP derived from Agtrap transgenic mice to Agtrap(-/-) recipient mice improved the systemic metabolic dysfunction.
Conclusions-These results demonstrate that Agtrap(-/-) mice are an effective model of metabolic disorders with visceral obesity and constitute evidence that ATRAP plays a protective role against insulin resistance, suggesting a new therapeutic target in metabolic disorders. Identification of ATRAP as a novel receptor binding modulator of adipose tissue inflammation not only has cardiovascular significance but may have generalized implication in the regulation of tissue function.

DOI： 10.1161/JAHA.113.000312

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

DOI： 10.1111/1744-9987.12032

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Authorship：Lead author,　Corresponding author   Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Purpose of review
Recent genome-wide association studies (GWAS) have revealed that the ATP2B1 gene is associated with hypertension not only in people of European origin, but also in Japanese, Chinese, and Koreans. However, ATP2B1 has never been considered to be a candidate gene for essential hypertension. Thus, this review summarizes the findings obtained in GWAS regarding the role of the ATP2B1 gene in essential hypertension, as well as recent suggestions about the mechanisms responsible for the effects of the ATP2B1 gene on calcium homeostasis. We also review the findings of studies involving spontaneously hypertensive rats and tissue-specific ATP2B1 knockout mice examining the effects of ATP2B1 on hypertension.
Recent findings
The ATP2B1 gene has been revealed to be a hypertension-susceptibility gene in large-scale GWAS studies. Meta-analysis of the ATP2B1 gene polymorphisms associated with hypertension confirmed that ATP2B1 is significantly associated with hypertension in East Asians. Moreover, vascular smooth muscle cell ATP2B1 knockout mice exhibited high blood pressure in radio telemetry-based experiments.
Summary
The ATP2B1 gene has been demonstrated to have a strong influence on blood pressure. Detailed analysis of tissue-specific knockout mice is expected to further confirm the role of ATP2B1 in the near future.

DOI： 10.1097/MNH.0b013e32835da4ca

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Language：Japanese   Publisher：Japanese Dermatological Association  

We present a case of a 49-year-old Japanese woman with recalcitrant pemphigus vulgaris associated with multiple severe infections and very high anti-desmoglein 1 and 3 antibody titers. The lesions covered more than 70% of her body surface area. A combination of repeated steroid pulse therapy, plasmapheresis, and IVIG could not control the disease. However, a single cycle of rituximab therapy led to complete remission for 18 months, during her steroid dose was tapered. No adverse effects have been observed till date. Rituximab is a chimeric murine?human monoclonal antibody that targets the CD20 antigen found on B cells andcauses rapid depletion of this cell population. It has been approved for the treatment of non-Hodgkin B-cell lymphoma and rheumatoid arthritis in the United States. In addition, rituximab has been shown to be effective for the treatment of other autoimmune diseases such as systemic lupus erythematosus and pemphigus. This treatment should be considered for recalcitrant cases with persistent high titers of autoimmune antibodies despite combination therapy with corticosteroids, immunosuppressive agents, plasmapheresis, and IVIG. It can also be considered for cases of recurrence due to tapering of steroids and immunosuppressive agents. However, the adverse effects of immunosuppression by rituximab should be carefully considered for each individual patient.

DOI： 10.14924/dermatol.123.415

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Data regarding renal disease in the elderly (age a parts per thousand yen65 years old) and very elderly (age a parts per thousand yen80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy.
From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed.
The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P &lt; 0.001), and IgAN was less common (P &lt; 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life.
Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

DOI： 10.1007/s10157-012-0673-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Residual renal function preservation in patients with renal failure has been shown to be related to better outcomes not only in the pre-dialysis phase but also after hemodialysis initiation. However, the effect of factors such as antihypertensive agents on residual renal function preservation has not been investigated adequately in prevalent hemodialysis patients. This study examined factors related to the rate of residual renal function preservation in 1-year hemodialysis patients who had residual renal function. We enrolled 191 consecutive maintenance hemodialysis patients who underwent hemodialysis for 1 year and maintained a urine output of more than 200 mL/day, to assess residual renal function loss. The rate of residual renal function loss was 19.9%. Multivariate analysis using residual renal function as the dependent variable revealed significant independent relationships with renin-angiotensin system inhibitor use (hazard ratio, 0.438; P = 0.027), history of cardiovascular disease (hazard ratio, 2.475; P = 0.024), and rate of weight gain between dialysis sessions (hazard ratio, 1.348; P = 0.013). No relationship was observed with calcium channel blocker use. Renin-angiotensin system inhibitor use, rate of body weight gain between dialysis sessions, and cardiovascular diseases are independently associated with residual renal function preservation in patients with residual renal function after 1 year of hemodialysis. A further intervention study is required to investigate whether treatment with renin-angiotensin system inhibitors and suppression of body weight gain preserves residual renal function for a longer time in hemodialysis patients.

DOI： 10.1111/j.1744-9987.2012.01087.x

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DOI： 10.1038/hr.2012.41

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na+-Ca2(+) exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells. (Hypertension. 2012;59:854-860.). Online Data Supplement

DOI： 10.1161/HYPERTENSIONAHA.110.165068

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background: We evaluated the effect of coadministration of beta-blocker (carvedilol) as the third agent with angiotensin II receptor blockers (ARB) and calcium channel blockers (CCB) on blood pressure (BP) regulation and glucose metabolism. Methods: Diabetic patients who did not achieve the therapeutic BP goal (140/90 mmHg) by ARB and CCB combination therapy were recruited. This study was designed to compare the BP regulating effects by adding carvedilol (10 mg/day, n = 30) and by doubling the dose of either ARB (n = 34) or CCB (n = 31). Serum glucose metabolism was examined. Results: The carvedilol group showed a decrease (P &lt; 0.01) in BP from 166 +/- 11/90 +/- 8 to 156 +/- 9/84 +/- 7 mmHg at 12 weeks. In the ARB and CCB groups, BP also decreased (P &lt; 0.01) from 164 +/- 11/87 +/- 8 to 153 +/- 10/83 +/- 8 and 163 +/- 7/87 +/- 8 to 153 +/- 8/84 +/- 9 mmHg at 12 weeks. The rates of achieving therapeutic goal at 12 weeks were 36.7% in the carvedilol, 38.2% in the ARB and 41.9% in the CCB group. Serum glucose metabolism did not change in all groups. Conclusions: These results suggest that adding carvedilol decreased BP as safely as increasing the dose of ARB or CCB in patients with diabetic nephropathy. Copyright (c) 2012 S. Karger AG, Basel

DOI： 10.1159/000341491

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Dialysis-related amyloidosis (DRA) is one of the major complications often seen in long-term dialysis patients, and is one of the factors that decreases quality of life. beta 2-microglobulin (beta 2-m) is considered to be a major pathogenic factor in dialysis-related amyloidosis. The Lixelle adsorbent column, with various capacities, has been developed to adsorb beta 2-m from the circulating blood of patients with dialysis-related amyloidosis. Using a minimum type of beta 2-m-adsorbing column (Lixelle S-15), we evaluated its therapeutic efficacy and safety in dialysis patients. Seventeen hemodialysis patients with DRA were treated with the S-15 column for one year. Treatment was performed three times a week in this study. During the study period, pinch strength, visual analog scale for joint pain, and activities of daily living were evaluated every three months, and blood sampling was performed every six months. After one year&apos;s treatment with the S-15 column, the beta 2-m level decreased from 29.3 +/- 9.6 mg/L to 24.7 +/- 5.1 mg/L (P &lt; 0.05), and the high sensitive C-reactive protein level decreased from 2996 +/- 4380 ng/mL to 1292 +/- 1774 ng/mL. After one year of S-15 column use, pinch strength increased from 5.9 +/- 3.0 pounds to 7.2 +/- 3.2 pounds (P &lt; 0.05), and the visual analog scale for joint pain and activities of daily living score also improved. Long-term use of the Lixelle S-15 column is safe and effective for improvement of quality of life in chronic dialysis patients. Improvement of chronic inflammation may be one of the mechanisms through which the beneficial effects of the column is effected.

DOI： 10.1111/j.1744-9987.2011.00937.x

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Background: Some trials have indicated that coronary artery calcification progresses more slowly in sevelamer-treated dialysis patients than in those using calcium-based binders. Effects of phosphate binders on circulating advanced glycation end products (AGEs) are unknown.
Study Design: Randomized trial with parallel-group design.
Setting & Participants: 183 adult (aged &gt; 20 years) patients on maintenance hemodialysis therapy at 12 dialysis facilities with a mean vintage of 118 +/- 89 (median, 108) months. Dialysate calcium concentration was 2.5 mEq/L, and dietary calcium was not controlled.
Intervention: Patients were randomly assigned to 12 months of treatment with sevelamer (n = 91) or calcium carbonate (n = 92).
Outcomes & Measurements: Primary outcome measures were change from baseline in coronary artery calcification score (CACS) determined at study entry and completion using multislice computed tomography and the proportion of patients with a &gt;= 15% increase in CACS. Blood parameters were determined at study entry and 2-week intervals, and levels of plasma pentosidine, a representative AGE, were determined at study entry, 6 months, and study completion.
Results: 79 (86.8%) and 84 (91.3%) patients in the sevelamer and calcium-carbonate arms completed the treatment, respectively. Both binders were associated with an increase in mean CACS: 81.8 (95% CI, 42.9-120.6) and 194.0 (139.7-248.4), respectively (P &lt; 0.001 for both). After adjustment for baseline values, the increase in the sevelamer group was 112.3 (45.8-178) less (P &lt; 0.001). Percentages of patients with a &gt;= 15% increase in CACS were 35% of the sevelamer group and 59% of the calcium-carbonate group (P = 0.002). Plasma pentosidine levels increased with sevelamer treatment (P &lt; 0.001). Sevelamer use was associated with decreased risk of a &gt;= 15% increase in CACS regardless of baseline blood parameters, pentosidine level, and CACS.
Limitations: Treatment duration was relatively short, some sevelamer-treated patients (7 of 79) received calcium carbonate, and washout could not be performed.
Conclusions: The data suggest that sevelamer treatment slowed the increase in CACS and suppressed AGE accumulation. Am J Kidney Dis. 57(3): 422-431. (C) 2011 by the National Kidney Foundation, Inc.

DOI： 10.1053/j.ajkd.2010.10.055

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Language：Japanese   Publisher：(株)日本メディカルセンター  

透析患者,保存期腎不全の患者は体内に余剰水分が貯留しやすい状態にあり,四肢の浮腫,胸水,腹水といった身体所見として現れる.身体所見および検査所見から患者の体液量を正確に把握し,適切な治療や栄養介入を行うことが重要である.正確な体液量を理解することにより,患者の生命予後の改善に役立てることができる.(著者抄録)

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3x10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1x10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9x10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4x10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6x10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension. (Hypertension. 2010;56:973-980.)

DOI： 10.1161/HYPERTENSIONAHA.110.153429

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Background: Several reports have found that chronic kidney disease (CKD) is an independent risk factor for stroke. However, little is known about whether cerebrovascular disease conversely predicts the outcome of kidney function. In view of the similarities between vascular beds of the kidney and brain, we hypothesized that silent brain infarction (SBI) could reflect the degree of injury in renal small vessels and predict the risk of progression of kidney disease.
Study Design: Prospective cohort study.
Setting & Participants: 142 patients with CKD (stages 3-5) admitted to our clinic for education about CKD from January 2006 to July 2007 were recruited and followed up for 2 years.
Predictor: SBI.
Outcomes: Composite primary outcomes: doubling of serum creatinine level, development of end-stage renal disease defined as dialysis or transplant, and death from cardiovascular causes. Secondary outcome: rate of decrease in estimated glomerular filtration rate.
Measurements: Brain magnetic resonance imaging was performed to determine the presence or absence of SBI.
Results: At baseline, 87 patients had SBI. During follow-up, 43 patients (30.3%) developed the following primary outcomes: doubling of serum creatinine level (8 patients), dialysis therapy (32 patients), and death from cardiovascular causes (3 patients). In crude analysis, the presence of SBI predicted time to primary outcomes (P = 0.01). A multivariate Cox model confirmed the presence of SBI to be an independent predictor of study outcomes (HR, 2.16; 95% CI, 1.01-4.64; P = 0.04). Estimated glomerular filtration rate decreased more in patients with SBI than in those without SBI (-0.11/y vs -0.06/y relative to baseline value; P = 0.005).
Limitations: Study size was small.
Conclusion: We showed that SBI was an important independent prognostic factor for the progression of kidney disease in patients with CKD. Our findings suggest that patients with SBI should be considered a high-risk population for decreased kidney function. Am J Kidney Dis 56: 468-476. (C) 2010 by the National Kidney Foundation, Inc.

DOI： 10.1053/j.ajkd.2010.03.018

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

We cloned a novel molecule interacting with angiotensin II type 1 receptor, which we named ATRAP (for angiotensin II type 1 receptor associated protein). Previous in vitro studies showed that ATRAP significantly promotes constitutive internalization of the angiotensin II type 1 receptor and further attenuates angiotensin II mediated hypertrophic responses in cardiomyocytes. The present study was designed to investigate the putative functional role of ATRAP in cardiac hypertrophy by angiotensin II infusion in vivo. We first examined the effect of angiotensin II infusion on endogenous ATRAP expression in the heart of C57BL/6J wild-type mice. The angiotensin II treatment promoted cardiac hypertrophy, concomitant with a significant decrease in cardiac ATRAP expression, but without significant change in cardiac angiotensin 11 type 1 receptor expression. We hypothesized that a downregulation of the cardiac ATRAP to angiotensin II type 1 receptor ratio is involved in the pathogenesis of cardiac hypertrophy. To examine this hypothesis, we next generated transgenic mice expressing ATRAP specifically in cardiomyocytes under control of the alpha-myosin heavy chain promoter. In cardiac-specific ATRAP transgenic mice, the development of cardiac hypertrophy, activation of p38 mitoen-activated protein kinase, and expression of hypertrophy-related genes in the context of angiotensin treatment were completely suppressed, in spite of there being no significant difference in blood pressure on radiotelemetry between the transgenic mice and littermate control mice. These results demonstrate that cardiomyocyte-specific overexpression of ATRAP in vivo abolishes the cardiac hypertrophy provoked by chronic angiotensin II infusion, thereby suggesting ATRAP to be a novel therapeutic target in cardiac hypertrophy. (Hypertension. 2010;55:1157-1164.)

DOI： 10.1161/HYPERTENSIONAHA.109.147207

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective-Low-density lipoprotein (LDL) apheresis is a potential therapy for conventional therapy-resistant peripheral artery disease. In the present study, we examined the chronic effects of LDL apheresis on clinical parameters in vivo and endothelial cell functions in vitro in hemodialysis patients who had the complication of peripheral artery disease.
Methods and Results-Twenty-five patients were enrolled, and the responses of 19 patients to LDL apheresis were analyzed. Patients were classified into 2 groups according to change in ankle-brachial pressure index (ABI) after treatment: patients with improved ABI (responders, n = 10) and patients with worsened ABI (nonresponders, n = 9). In the responders, apheresis resulted in a long-term reduction of circulating levels of oxidized LDL, C-reactive protein, and fibrinogen. In human umbilical vein endothelial cells (HUVECs), the serum from the responders increased expression of activated endothelial nitric oxide synthase protein and proliferative activity. Furthermore, there was a significant correlation between ABI and activated endothelial nitric oxide synthase protein level in HUVECs treated with responder serum (R = 0.427, P &lt; 0.05).
Conclusion-These results demonstrate that LDL apheresis decreases oxidized LDL and inflammation and improves endothelial cell function in the responders. This may be one of the mechanisms involved in the long-term therapeutic effect of LDL apheresis on peripheral circulation in hemodialysis patients. (Arterioscler Thromb Vasc Biol. 2010;30:1058-1065.)

DOI： 10.1161/ATVBAHA.109.200212

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INFORMA HEALTHCARE  

Objectives: Small dense low-density lipoprotein (LDL) plays an important role in glomerular injury through conversion to an oxidatively modified form of LDL. However, few studies have evaluated the effects of antilipidemic agents on the LDL particle size and renal function in hyperlipidemic patients with nondiabetic nephropathy. Methods: This study was a randomized crossover trial comparing the effects of atorvastatin (10 mg/day) and probucol (500 mg/day) administered for 24 weeks in 31 patients (urinary albumin excretion 0.3-2.0 g/day and creatinine clearance &gt; 30 mL/min/1.73 m(2)). Lipid parameters, mean LDL particle diameter, creatinine clearance, and urinary albumin to creatinine excretion ratio were measured before and during treatment periods. Main findings: Atorvastatin and probucol significantly reduced the serum total cholesterol and LDL cholesterol concentrations. When stratified by mean baseline LDL particle size at 25.5 nm, atorvastatin increased (p &lt; 0.05) LDL particle size from 24.6 +/- 0.5 to 25.2 +/- 0.9 nm only in the &lt;25.5 nm (pattern B) group, whereas probucol decreased (p &lt; 0.05) LDL size from 24.8 +/- 0.9 to 24.2 +/- 0.9 nm in the pattern B group and from 25.9 +/- 0.5 to 24.6 +/- 0.8 nm in the &gt;= 25.5 nm (pattern A) group. No significant differences in urinary albumin/creatinine excretion ratio and creatinine clearance were observed in both groups during treatment. Conclusions: Only atorvastatin improved the LDL-subtype distribution in hyperlipidemic patients with nondiabetic nephropathy, although both agents exhibited no renoprotective action, suggesting that the effects on LDL-subtype distribution do not directly lead to renoprotection.

DOI： 10.3109/0886022X.2010.486493

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ATHEROSCLEROSIS SOC  

Aim: We previously identified a quantitative trait locus (QTL) on rat chromosome 5 that appeared to be primarily controlled by the sympathetic nervous system. Because sympathetic overactivity is related to hypertension, solute carrier family 6, member 9 (SLC6A9) is a candidate gene for the connection of this QTL with blood pressure regulation. In the present study, we therefore explored the role of SLC6A9 genetic variations in human essential hypertension (EH).
Methods: We evaluated three single nucleotide polymorphisms (SNPs) (rs2286245, rs3791124 and rs2486001) in 758 essential hypertension patients and 726 controls. Polymorphism-related genotypes were determined with TaqMan assays.
Results: The allelic frequency of rs2286245 (C versus T, p=0.032) showed significant differences between EH and normotensive controls (NT) groups. The genotypic distribution of rs3791124 in its dominant model (AA + GA versus GG, p = 0.027) also showed significant differences between EH and NT groups. The genotype and allele distributions of rs2486001 did not exhibit any significant differences.
Conclusion: We found an association between SLC6A9 gene polymorphisms and essential hypertension in a Japanese population, suggesting that SLC6A9 is a susceptibility locus for essential hypertension.

DOI： 10.5551/jat.E125

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

In non-diabetic patients with nephrotic syndrome (NS) at early stages of chronic kidney disease, it remains unclear whether the degree of proteinuria affects the nocturnal blood pressure (BP) dip. We evaluated the relationship among circadian BP rhythm, proteinuria and hypoalbuminemia in these patients. We also evaluated the autonomic nervous activity. Twenty-four-hour BP was measured in NS patients (8 men and 13 women; mean age, 58.5 +/- 14.8 years) and age- and sex-matched normal subjects (11 men and 13 women; mean age, 54.3 +/- 18.2 years) as controls. Serum albumin and urinary protein concentrations were measured. Power spectral analysis of the heart rate was performed, and the high frequency (HF) and low frequency (LF) components were calculated as indices of sympathovagal balance. There were no differences in waking BP between the NS and the control groups (131 +/- 13/78 +/- 9 vs. 130 +/- 17/76 +/- 7 mm Hg; P&gt;40.05). However, sleeping BP was significantly higher in the NS group than in the control group (127 +/- 18/75 +/- 9 vs. 115 +/- 14/66 +/- 7 mm Hg; P&lt;0.05). Sleeping/waking BP ratios were higher in the NS group than in the control group (P&lt;0.01). In the NS group, these ratios correlated significantly with serum albumin level (r = -0.54, P = 0.011 for systolic BP; r = -0.48, P = 0.030 for diastolic BP) and urinary protein excretion (r = 0.47, P = 0.027 for systolic BP; r = 0.60, P = 0.003 for diastolic BP). Both HF components and LF/HF ratios were not significantly different between the two groups. In non-diabetic NS patients, loss of nocturnal BP reduction correlates with proteinuria and hypoalbuminemia but not with circadian autonomic nervous rhythm. Hypertension Research (2009) 32, 364-368; doi:10.1038/hr.2009.21; published online 20 March 2009

DOI： 10.1038/hr.2009.21

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Backgrounds. Urinary excretions of lipocalin-type prostaglandin D synthase/beta-trace (L-PGDS) probably reflect the increased permeability of injured glomerular capillary walls of the kidney. We tested the hypothesis in cross-sectional and prospective studies that urinary L-PGDS excretions predict renal injury in type-2 diabetes.
Methods. (1) In the cross-sectional studies, we evaluated whether urinary L-PGDS excretions were able to predict renal diseases in a pooled population including 793 healthy subjects and 200 patients with various forms of renal diseases. (2) We determined the cut-off point of urinary L-PGDS excretions to predict &gt;= 30 mg/gCr albuminuria in 666 patients with type-2 diabetes. (3) In the prospective study, 121 type-2 diabetic patients with &lt; 30 mg/gCr albuminuria were followed for almost 2 years to examine whether urinary L-PGDS excretions predict the future status of renal injury in type-2 diabetes.
Results. (1) In the cross-sectional studies, receiver operating characteristic analysis revealed that urinary L-PGDS excretions better predicted the patients with kidney diseases than the other markers of renal injury. (2) It was also demonstrated that &gt;= 4.2 mg/gCr urinary L-PGDS excretions better predicted &gt;= 30 mg/gCr albuminuria in type-2 diabetic patients than other markers. (3) The prospective study revealed that in type-2 diabetic patients with &lt; 30 mg/ gCr albuminuria, the patients with &gt;= 4.2 mg/gCr urinary L-PGDS excretions more likely exhibited the renal injury during the follow-up periods than those with &lt; 4.2 mg/gCr urinary L-PGDS excretions.
Conclusions. Urinary L-PGDS excretions reflect the current increased permeability of injured glomerular capillary walls and better predict the future status of renal injury in type-2 diabetes with &lt; 30 mg/gCr albuminuria.

DOI： 10.1093/ndt/gfn515

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background. The presence of silent brain infarction (SBI) increases the risk of symptomatic stroke and dementia. The association between SBI and chronic kidney disease (CKD) has not been clarified. Moreover, little is known about what factors are related to SBI in CKD patients and whether the prevalence of SBI differs in CKD stage or cause of CKD.
Methods. This is a cross-sectional study. A total of 375 subjects-025EF335 with CKD and 40 with essential hypertension-025EFwere included. All subjects underwent magnetic resonance imaging (MRI) of the brain to detect SBI. Glomerular filtration rate (GFR) was estimated using Modification of Diet in Renal Disease equation, and cardiovascular risk factors were examined.
Results. The prevalence of SBI was 56.5% in all subjects. Among causes of CKD, hypertensive nephrosclerosis had a strong association with SBI. According to the estimated GFR (eGFR) stage, the more severe the stage of eGFR, the higher the prevalence of SBI (age-adjusted odds ratio [95% confidence interval] for eGFR 30-59, 15-29 and &lt; 15 versus &gt;= 60 mL/min/1.73 m(2): 1.34 [0.68-1.99], 1.94 [1.30-2.57] and 2.51 [1.91-3.10]). In multivariate logistic analysis, eGFR was related to SBI independently, in addition to age and blood pressure (P = 0.025). However, other traditional and non-traditional risk factors were not.
Conclusion. There was an independent association between eGFR and SBI. CKD patients should receive active detection of SBI and more intensive preventive management, especially for hypertension, should be needed in CKD patients to prevent SBI.

DOI： 10.1093/ndt/gfn419

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DOI： 10.1159/000178764

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL PUBLISHING, INC  

Peritoneal calcification in three patients on continuous ambulatory peritoneal dialysis (CAPD) was reviewed, and the relation between the localization and extent of calcium deposits detected by abdominal computed tomography (CT) and clinical signs was evaluated. Case 1 was a 48-year-old man with abdominal pain, hemoperitoneum and secondary hyperparathyroidism after receiving CAPD for seven years. An abdominal CT revealed linear peritoneal calcification in the pelvic cavity and liver surface, and his symptoms resolved after switching to hemodialysis. His clinical course and pathological findings were compatible with those in progressive calcifying peritonitis. Case 2 was a 26-year-old man presenting with abdominal pain, vomiting and fullness two years after switching to hemodialysis, because of uncontrolled overhydration following 13 years of CAPD. Plaque-like calcification outlining the small intestine and parietal peritoneum was noted on CT Case 3 was a 59-year-old mail who had abdominal distention, vomiting and diarrhea three months after switching to hemodialysis due to loss of peritoneal function following 10 years of CAPD. CT revealed diffuse sheet-like calcification surrounding the bowel and mesentery, adherent dilated bowel loops and ascites. These CT findings Suggested the existence of encapsulating peritoneal sclerosis (EPS) in cases 2 and 3. Findings from our three patients indicate that peritoneal calcification is not always accompanied by EPS; however, monitoring peritoneal calcification and other findings by abdominal CT, even after cessation of CAPD, is crucial to maintain vigilance on whether the subclinical signs, which are temporally diagnosed as progressive calcifying peritonitis, advance to EPS.

DOI： 10.1111/j.1744-9987.2008.06620.x

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

BACKGROUND We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans.
METHODS We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data.
RESULTS The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences.
CONCLUSION We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.

DOI： 10.1038/ajh.2008.40

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

BACKGROUND We have earlier identified a quantitative trait locus (QTL) on rat chromosome 5 that appears to be primarily under the control of the sympathetic nervous system. Because sympathetic overactivity is related to both hypertension and insulin resistance, FABP3 is a candidate gene for the link between this QTL and blood pressure regulation. In this study, therefore, we explored the role of FABP3 genetic variations in essential hypertension (EH) in humans.
METHODS We evaluated two single-nucleotide polymorphisms (SNPs) (rs2279885 and rs2271072) in 758 patients with EH and 726 controls. Polymorphism-related genotypes were determined using TaqMan assays, while haplotypes were estimated from the genotype data.
RESULTS The frequencies of occurrence of the G allele of rs2279885 and the C allele of rs2271072 were significantly higher in subjects with EH than in normotensive (NT) subjects (P = 0.0339, P = 0.0209, respectively). However, the genotype distributions did not exhibit any significant differences.
CONCLUSION We found an association between FABP3 gene polymorphisms and EH in a Japanese population, thereby suggesting that FABP3 is a susceptibility locus for EH.

DOI： 10.1038/ajh.2008.40

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Language：Japanese   Publisher：Japanese Society for Apheresis  

Epidermolysis bullosa acquisita (EBA) is a comparatively rare autoimmune disease producing blisters at the subepidermal area similarly to bullous pemphigoid. Corticosteroid therapy is the first treatment of choice. However, the disease is refractory to such treatment in more than half of patients. Here, we treated 2 patients initially with systemic corticosteroids and then in combination with double filtration plasmapheresis (DFPP), which proved effective in both cases. The efficacy of DFPP has also been reported in 4 other Japanese cases. Therefore, we believe that it is important to immed...

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background Essential hypertension is a complex disorder that results from the interaction of a number of susceptibility genes and environmental factors. The TNFRSF4 (tumor necrosis factor receptor superfamily, member 4) gene was one of the genes that showed altered renal expression in long-term salt loading in mice. Moreover, association of the TNFRSF4 and TNFSF4 (tumor necrosis factor (ligand) superfamily, member 4) genes with myocardial infarction was recently reported. Since essential hypertension is a well-known risk factor for myocardial infarction, we hypothesized that TNFRSF4 could be a susceptibility gene for essential hypertension.
Methods We performed a case -control study of TNFRSF4 in two independent population.
Results Extensive investigation of single nucleotide polymorphisms of the entire gene suggested that it resided in one linkage disequilibrium block, and four single nucleotide polymorphisms in the 50 flanking region sufficiently represented major haplotypes. In the combined population, the frequency of the most frequent haplotype, C-C-A- A, was significantly lower (P = 8.07 X 10(-5)) and that of the second most frequent haplotype, C-T-G-A, was significantly higher (P = 6.07 X 10(-4)) in hypertensive subjects than in control subjects. This difference was observed only in female patients. The C-T-G-A haplotype showed a lower promoter activity than other haplotypes, suggesting a relationship with disease susceptibility.
Conclusion Our results suggest that TNFRSF4 is a female-specific susceptible gene for essential hypertension.

DOI： 10.1097/HJH.0b013e3282f6a65e

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

A multiple candidate-gene approach was used to investigate not only candidate genes, but also candidate pathways involved in the regulation of blood pressure. We evaluated 307 single nucleotide polymorphisms (SNPs) in 307 genes and performed an association study between 758 cases and 726 controls. Genes were selected from among those encoding components of signal transduction pathways, including receptors, soluble carrier proteins, binding proteins, channels, enzymes, and G-proteins, that are potentially related to blood pressure regulation. In total, 38 SNPs were positively (p&lt;0.05) associated with hypertension. Replication of the findings and possible polygenic interaction was evaluated in five G-protein-related positive genes (GN12, GNA14, RGS2, RGS19, RGS20) in a large cohort population (total n=9,700, 3,305 hypertensives and 3,827 normotensive controls). In RGS20 and GNA14, dominant models for the minor allele were significantly associated with hypertension. Multiple dimension reduction (MDR) analysis revealed the presence of gene-gene interaction between GNA14 and RGS20. The MDR-proved combination of two genotypes showed a significant association with hypertension ( X-2= 9.939 p=0.0016) with an odds ratio of the high-risk genotype of 1.168 (95% confidence interval [CI] [1.061-1.287]). After correction for all possible confounding parameters, the MDR-proved high-risk genotype was still a risk for hypertension (p=0.0052). Furthermore, the high-risk genotype was associated with a significantly higher systolic blood pressure (133.08 +/- 19.46 vs. 132.25 +/- 19.19 mmHg, p=0.04) and diastolic blood pressure (79.65+/-11.49 vs. 79.01+/-11.32 mmHg, p=0.019) in the total population. In conclusion, a systemic multiple candidate gene approach can be used to identify not only hypertension-susceptibility genes but also hypertension-susceptibility pathways in which related genes may synergistically collaborate through gene-gene interactions to predispose to hypertension.

DOI： 10.1291/hypres.31.203

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

Sevelamer improves hyperphosphatemia without increasing the calcium load. However, it remains unknown whether sevelamer restores bone metabolism in hemodialysis patients with low bone turnover osteodystrophy and hypoparathyroidism. We investigated the changes in serum intact parathyroid hormone (iPTH) and bone metabolic marker levels after replacing calcium carbonate with sevelamer in these patients. We also conducted stratified analysis based on patient background and multivariate analysis to determine the factors affecting these parameters. During sevelamer replacement therapy, serum calcium and phosphate concentrations, and the calcium phosphate product were measured at 0, 1, 3, and 6 months. Serum iPTH, bone alkaline phosphatase and osteocalcin concentrations were measured at 0 and 6 months. In hemodialysis patients (71 men and 46 women, 63 +/- 12 years old) serum calcium levels and the calcium phosphate product decreased significantly at 1 month. Serum iPTH, bone alkaline phosphatase and osteocalcin levels increased significantly at 6 months. Increases in serum iPTH concentrations were observed in all stratified groups. Significant increases in serum bone alkaline phosphatase and osteocalcin concentrations were found only in the relative hypoparathyroidism group (iPTH levels &gt;= 51.5 pg/mL, the median pretreatment level). Multivariate analysis showed that the factors affecting change in serum iPTH level are baseline serum iPTH, baseline calcium level (&gt;= 9.5 mg/dL), and dialysis duration of 10 years or longer. Sevelamer appears useful for the treatment of hyperphosphatemia in these patients. Particularly, in the relative hypoparathyroidism group, the iPTH secretory response is probably enhanced and bone turnover may have been improved as a result of reducing the calcium load.

DOI： 10.1111/j.1744-9987.2007.00524.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC INVESTIGATIVE PATHOLOGY, INC  

The recently identified endogenous peptide apelin and its specific apelin receptor (APJ) are currently being considered as potential regulators in vascular tissue. Previously, we reported apelin mediates phosphorylation of myosin light chain and elicits vasoconstriction in vascular smooth muscle. In this study, physiological roles of the apelin-APJ system were investigated on atherosclerosis. In APJ and apolipoprotein E double-knockout (APJ(-/-)ApoE(-/-)) mice fed a high-cholesterol diet, atherosclerotic lesions were dramatically reduced when compared with APJ(+/+) ApoE(-/-) mice, in the absence of an effect of cholesterol levels. Immunohistochemical detection of smooth muscle cells, using a smooth muscle a-actin antibody, showed greatly reduced staining for these cells in lesions of APJ(+/+)ApoE(-/-) mice fed a highcholesterol diet. Vascular production of superoxide radicals and the expression of nicotinamide-adenine dinucleotide phosphate oxidase subunits were decreased in APJ(-/-)ApoE(-/-) mice compared with APJ(+/+)ApoE(-/-) mice fed a standard normal diet. in vascular smooth muscle cells, apelin induced nicotinamide-adenine dinucleotide phosphate oxidase subunit expression. Apelin also induced vascular smooth muscle cell proliferation, which was inhibited by superoxide dismutase or diphenylene iodonium. The apelin-APJ system is a mediator of oxidative stress in vascular tissue, and thus we propose it to be a critical factor in atherogenesis under high-cholesterol dietary conditions. APJ deficiency is preventative against oxidative stresslinked atherosclerosis.

DOI： 10.2353/ajpath.2007.070471

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

The ubiquitin ligase, NEDD4L, participates in plasma volume and blood pressure regulation by controlling cell surface expression of kidney epithelial sodium channel (ENaC). Impairment of ENaC internalization with disrupting Nedd4L binding PY motif in the C-terminal of the protein showed rare Mendelian human hypertension disorder, Liddle syndrome. Therefore, possible involvements of ENaC-Nedd4L system abnormalities were suggested in development of human hypertension. Previously, we discovered a common variant, named v13(G/A), that affects the formation of an evolutionally new C2-encoding isoform of the Nedd4L gene in humans. The aim of this study was to test a hypothesis whether this variant is involved in essential hypertension; we performed the association study in a sample of the Japanese population. We found a gender-specific genotypic and allelic association with statistical significance achieved only in males. Our data suggest that this Genetic variation may contribute to essential hypertension in Japanese male patients through the mechanism of disrupting the C2 encoding isoform in vivo. Furthermore, molecular and functional studies will be required to elucidate the mechanism by which genetic variation in NEDD4L contributes to the development of essential hypertension.

DOI： 10.1111/j.1447-0594.2007.00382.x

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

During the past decade, considerable efforts and resources have been devoted to elucidating the multiple genetic and environmental determinants responsible for hypertension and its associated cardiovascular diseases. The success of positional cloning, fine mapping, and linkage analysis based on whole-genome screening, however, has been limited in identifying multiple genetic determinants affecting diseases, suggesting that new research strategies for genome-wide typing may be helpful. Disease association (case-control) studies using microsatellite markers, distributed every 150 kb across the human genome, may have some advantages over linkage, candidate, and single nucleotide polymorphism typing methods in terms of statistical power and linkage disequilibrium for finding genomic regions harboring candidate disease genes, although it is not proven. We have carried out genome-wide mapping using 18 977 microsatellite markers in a Japanese population composed of 385 hypertensive patients and 385 normotensive control subjects. Pooled sample analysis was conducted in a 3-stage genomic screen of 3 independent case-control populations, and 54 markers were extracted from the original 18 977 microsatellite markers. As a final step, each single positive marker was confirmed by individual typing, and only 19 markers passed this test. We identified 19 allelic loci that were significantly different between the cases of essential hypertension and the controls.

DOI： 10.1161/01.HYP.0000257256.77680.02

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Evidence suggests a relationship between short-term blood pressure (BP) variability and cardiovascular target-organ damage. Although a blunted nocturnal decrease in BP and reduced heart rate variability have been shown to be associated with cardiovascular morbidity in diabetic patients, little information is available on short-term BP variability. In this study, short-term BP variability was assessed in 36 subjects with type 2 diabetes and overt nephropathy who underwent ambulatory BP monitoring, and the factors that correlated with short-term BP variability were examined. The incidence of coronary artery disease (CAD) was significantly greater in the patients with increased 24-h systolic BP variability (67% versus 11%; p &lt; 0.0005), while that of cerebrovascular disease was not significantly affected (61% versus 50%). Multiple stepwise regression analysis revealed that serum cholesterol (cholesterol) and plasma norepinephrine (p-NE) were significant and independent contributors to nighttime systolic BP variability (partial R-2 = 0.490, p &lt; 0.001; partial R-2 = 0.470, p &lt; 0.001) and demonstrated that body mass index and p-NE were primary determinants of nighttime diastolic BP variability (partial R-2 = 0.539, p &lt; 0.0005; partial R-2 = 0.304, p &lt; 0.05). Diabetic nephropathy patients with CAD had significantly increased daytime systolic (17.8 mmHg versus 13.1 mmHg, p &lt; 0.0005), nighttime systolic (17.4 mmHg versus 10.5 mmHg, p &lt; 0.0001), and nighttime diastolic (10.4 mmHg versus 7.2 mmHg, p &lt; 0.05) BP variability. Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CAD (odds ratio 3.13 [95% CI 1.02 - 9.61]; p &lt; 0.05). The increase in nighttime BP variability is associated with a proportional sympathetic activation in diabetic nephropathy. Elevated short-term BP variability combined with relative sympathetic prevalence during the night might represent an important risk factor for cardiovascular events in the diabetic population.

DOI： 10.1080/10641960601096760

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Inactivating mutations in the follicle-stimulating hormone receptor (FSHR) gene have been reported to cause hereditary hypergonadotropic ovarian failure. It has been found recently that the FSHR knockout mouse exhibits hypertension. The aim of the present study was to investigate the association between polymorphisms in the human FSHR gene and essential hypertension (EH) by using single nucleotide polymorphisms (SNPs). We selected 5 SNPs in the gene (rs1394205, rs2055571, rs11692782, rs1007541, and rs2268361) and performed 2 genetic case-control studies in different populations. A confirmative case-control study was performed using 1035 EH patients and 1058 age-matched controls. Transcriptional activities were measured with a luciferase assay system. The first case-control study found that the A allele of rs1394205 was significantly higher in EH females (P=0.010). In addition, in the confirmative case-control study, there was a significant difference for this SNP between female normotensive subjects (44.5%) and EH patients (50.7%) (P=0.043). Multiple logistic regression analysis in female subjects also revealed a significant association of subjects with the A allele of rs1394205 with EH (P=0.033), with the odds ratio calculated as 1.68 (95% CI: 1.04 to 2.73). Transcriptional activity of the A allele was 56 +/- 8% (mean +/- SD) of that observed for the G-type allele (P=0.001). Serum estradiol levels were significantly lower in patients with the A/A genotype than in patients without the A/A genotype (P=0.004). The SNP in the 5'-untranslated region of the FSHR gene affects levels of transcriptional activity and is a susceptibility mutation of EH in women.

DOI： 10.1161/01.HYP.0000233877.84343.d7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

Background. Otsuka Long-Evans Tokushima Fatty (OLETF) rats genetically develop diabetes which is associated with hypertension. In preliminary studies, urinary excretions of L-PGDS (lipocaline-type prostaglandin D synthase) increase before diabetic nephropathy obviously develops, and this may predict progression of renal injury following diabetes. In the present study, we attempted to define whether urinary excretions of L-PGDS behave as the predictor of development of diabetic nephropathy in OLETF rats.
Methods. We investigated alterations of urinary L-PGDS excretions during the establishment of diabetes and assessed the relationship between the L-PGDS excretions and renal function in OLETF rats. Furthermore, we treated OLETF rats with troglitazone and analysed the effects on L-PGDS metabolisms. Urinary L-PGDS was measured by immunoenzyme assay and the occurrence of L-PGDS and its mRNA in the kidney was assessed by immunohistochemistry and a PCR method.
Results. Urinary excretions of L-PGDS were significantly higher in OLETF rats than non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. The excretions age-dependently increased in OLETF and this increase appeared to be due to increased glomerular permeability to L-PGDS. Messenger RNA and antigenicity of L-PGDS were demonstrated in renal tissue; however, the de novo synthesis of L-PGDS mRNA seemingly contributed to urinary L-PGDS excretions much less than glomerular filtration. Multiple regression analysis revealed that urinary L-PGDS was determined by urinary protein excretions, and not by high blood pressure per se. Conversely, urinary proteinuria in the established diabetic nephropathy was predicted by urinary L-PGDS excretions in the early stage of diabetes.
Conclusions. Urinary excretions of L-PGDS are likely to reflect the underlying increase in glomerular permeability. This property may be useful to predict forthcoming glomerular damage following diabetes in OLETF rats.

DOI： 10.1093/ndt/gfk009

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：日本ベーリンガーインゲルハイム(株)  

75歳女.微熱が出現し,内服処方を受けたが改善なく,熱は38℃以上となり,食欲不振も認めたため,急性腎不全の疑いで入院した.Levine III/IVの収縮期雑音を聴取し,呼吸音正常肺胞呼吸音,ラ音なし,腹部平坦軟,圧痛なし,腫瘤触知せず,浮腫,皮疹・紫斑はなかった.組織所見はIgA腎症の予後不良群と診断されたが,臨床経過は血管炎症候群を特に顕微鏡的多発血管炎(MPA)が疑がわれた.症例はIgA腎症にMPAを合併し,ステロイド加療により良好な経過をたどった1例と考えられた.又,電子顕微鏡上,瘤様の高電子密度沈着物を認め,瘤を認めた半月体形成性糸球体腎炎と診断した

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The renin-angiotensin system in the kidney plays a critical role in the regulation of renal hemodynamics and sodium handling through the activation of vascular, glomerular and tubular angiotensin II type 1 (AT1) receptor-mediated signaling. We previously cloned a molecule that specifically bound to the AT1 receptor and modulated AT1 receptor signaling in vitro, which we named ATRAP ( for AT1 receptor-associated protein). The purpose of this study is to analyze the renal distribution of ATRAP and to examine whether ATRAP is co-expressed with the AT1 receptor in the mouse kidney. We performed in situ hybridization, Western blot analysis, and immunohistochemistry to investigate the expression of ATRAP mRNA and protein in the mouse kidney. The results of Western blot analysis revealed the ATRAP protein to be abundantly expressed in the kidney. Employing in situ hybridization and immunohistochemistry, we found that both ATRAP mRNA and the protein were widely distributed along the renal tubules from Bowman's capsules to the inner medullary collecting ducts. ATRAP mRNA was also detected in the glomeruli, vasculature, and interstitial cells. In all tubular cells, the ATRAP protein colocalized with the AT1 receptor. Finally, we found that the dietary salt depletion significantly decreased the renal expression of ATRAP as well as AT1 receptor. These findings show ATRAP to be abundantly and broadly distributed in nephron segments where the AT1 receptor is expressed. Furthermore, this is the first report demonstrating a substantial colocalization of ATRAP and AT1 receptor in vivo.

DOI： 10.1038/sj.ki.5000130

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Other Link： http://orcid.org/0000-0002-2657-2555

Language：Japanese   Publishing type：Research paper (international conference proceedings)  

Objectives: The purpose of this study was to investigate the clinical effects of low density lipoprotein (LDL) apheresis for the treatment of peripheral arterial disease (PAD) in the patients undergoing hemodialysis. Methods: Eleven patients suffering from PAD were treated with ten sessions of LDL apheresis. The absolute walking distance, ankle brachial blood pressure index (ABI), and serum levels of lipids and chemokines were assessed at baseline, at the tenth session, and three months after the end of the treatment. Results: The absolute walking distance and ABI significantly improved after ten sessions of apheresis and the walking distance remained to be longer even at three months after the end of the treatment. Subsequently, patients were assigned to two groups according to the change of ABI at three months after the end of the treatment
patients with improved ABI (ABI responders, n = 7), patients with worsened ABI (ABI non-responders, n = 4). The absolute walking distance also tended to increase in the ABI responders at three months after the end of the treatment, but did not increase in the ABI non-responders. Even at the tenth session of LDL apheresis, the serum levels of oxidized LDL significantly decreased, and malondialdehyde-modified (MDA)-LDL and fibrinogen also remained to be lower in the ABI responders. Conclusion: These results suggest that LDL apheresis not only decreases serum levels of lipids, but also inhibits the inflammation and oxidized stress in the patients suffering from PAD and undergoing hemodialysis.

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER DIABETES ASSOC  

Editor's comment: The editorial committee of Diabetes Care had some ethical concerns about potentially leaving patients for up to 24 weeks with blood pressure between 140190 and 2001110 mmHg. After careful consideration, we decided to publish this article for the following reasons. First, the scientific information was considered valid and important. Second, the study was passed by the institutional review board (IRB) of the investigators. The study was passed by their institution at a time when perhaps ethical guidelines were not as stringent. Third, in response to queries by the editorial committee, the investigators pointed out that other hypertension studies initiated at around that time also had similar protocols. The editorial Committee then dealt with the general issue of different criteria utilized by different IRBs around the world. Although the editorial committee will continue to be sensitive to decisions by various IRBs, investigators should realize that the more recent, stricter guidelines will also be considered by the editorial committee should ethical concerns be raised in the review process.
OBJECTIVE - Few studies have assessed whether 24-h blood pressure control induced by antiltypertensive agents improves macroalbuminuria in hypertensive type 2 diabetic patients with overt nephropathy. We evaluated the effects of losartan and amlodipine on 24-h blood pressure, autonomic nervous activity, and albuminuria in these patients.
RESEARCH DESIGN AND METHODS - in this open-label, parallel-prospective, randomized study, 44 patients were treated with losartan and 43 with amlodipine for a 12-week titration phase and a maintenance phase for a maximum of 12 weeks. Twenty-four-hour blood pressure and urinary albumin excretion were measured before and during treatment. Simultaneously, power spectral analysis of heart rate was performed to evaluate low frequency (LF) and high frequency (HF) components and LF-to-HF ratios as an index of sympathovagal balance.
RESULTS - Losartan decreased (P &lt; 0.001) mean blood pressure from 162/91 to 150/82 mmHg during daytime and from 146/82 to 137/74 mmHg during nighttime (systolic/diastolic). Amlodipine also decreased (P &lt; 0.001) blood pressure from 159/90 to 147/82 mmHg during daytime and from 143/81 to 131/72 mmHg during nighttime. LF and HF components and nighttime-to-daytime ratios for the LF-to-HF ratios did not differ during treatment in two groups, showing no changes in the diurnal autonomic nervous rhythm. Losartan decreased (P &lt; 0.001) 24-h urinary albumin excretion from 810 mg/day (95% CI 780-1,140) to 570 (510910). Amlodipine, however, did not decrease (P = 0.893) albuminuria (790 mg/day [7801,170] vs.790 [710-1,260]).

DOI： 10.2337/diacare.28.8.1862

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Language：English   Publisher：OXFORD UNIV PRESS  

DOI： 10.1093/ndt/gfh838

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Recent reports suggest the relationship of short-term blood pressure (BP) variability to cardiovascular target organ damage. In this study, short-term BP variability was assessed as the standard deviation of daytime and nighttime BP in 36 hospitalized patients with chronic renal failure (CRF) who underwent ambulatory BP monitoring. Positive correlations were observed between body mass index (BMI) and daytime systolic and diastolic BP variability, BMI and nighttime diastolic BP variability, cholesterol and daytime systolic BP variability, cholesterol and nighttime systolic and diastolic BP variability, nocturnal decline in BP and nighttime diastolic BP variability, and plasma concentration of norepinephrine (P-NE) and nighttime systolic BP variability. In multivariate linear regression analyses, BMI showed the strongest association with daytime and nighttime diastolic BP variability (p &lt;.005 and p &lt;.05). On the other hand, cholesterol and p-NE were the primary determinants of daytime and nighttime systolic BP variability, respectively (p &lt;.01 and p &lt;.0005). Interestingly, CRF patients with ischemic heart disease (IHD) had significantly increased daytime systolic and diastolic BP variability and nighttime systolic BP variability (p &lt;.05 or less). Furthermore, logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor of IHD in patients with CRF (odds ratio 1.50 [95% confidence interval 1.01 to 2.25]; p &lt;.05). Taken together, short-term BP variability is suggested to be affected by BMI, cholesterol, and p-NE in CRF patients. Furthermore, sympathetic nerve overactivity may be involved in cardiovascular complications in CRF patients through the increase in nighttime systolic BP variability.

DOI： 10.1081/CEH-200048738

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Increased resting heart rate (HR) and increased sympathetic nervous activity are independent risk factors for cardiovascular disease. Recently, base heart rate (HRo: minimum stable HR during sleep) has been reported to relate to cardiac stroke volume and age. However, little is known about the relevance of HRo. The aim of our study was to evaluate how HRo is associated with HR variability (HRV), blood pressure and health-related quality of life (HRQOL) in healthy subjects. A total of 139 volunteers participated in this study that measured 24-hr HR, HRV, and blood pressure. HRo was estimated from the trendgram and the histogram of HR during the nighttime (sleep) period, and calculated as the 1% lowest value of its integral. HRQOL was assessed by Medical Outcome Study Short-Forum 36-Item Health Survey. Sympathetic nervous activity (ratio of low frequency to high frequency component: LF/HF) and parasympathetic nervous activity (high frequency component: HF) were calculated by ECG monitoring. HRo was positively correlated with 24-hr LF/HF and nighttime LF/HF. HRo was negatively correlated with 24-hr HF and nighttime HF. Moreover, HRo was positively correlated with the scores of social functioning and role-physical. Using multivariate analysis, HRo is related to LF/HF, body mass index, and the score of social functioning (HRQOL). HRo may be a useful indicator for assessing sympathetic nervous activity and HRQOL in normotensive healthy subjects.

DOI： 10.1081/CEH-200048749

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Although vascular smooth muscle cells (VSMCs) are widely used in cardiovascular research, their phenotypic change under various culture conditions is problematic to evaluate the experimental results obtained. The levels of angiotensin (Ana) type 1/2 (ATI/AT2) receptors as well as contractile and structural proteins are degraded through culture passages. The present study demonstrated that heparin recovered Ang receptors and differentiation markers, such as desmin, SM-22 and smooth muscle a-actin in VSMCs at the ninth passage. Heparin also potenciated Ang II-induced activation for ERK1/2 and p38. These results suggest a potential value of heparin-treated VSMCs as the model for analysis of Ang-inediated signal transduction under physiological condition. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.febslet.2004.11.093

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The effects of altered dietary salt intake and/or hydralazine-induced hypotension on renal endothelial nitric oxide synthase (eNOS) expression were determined in angiotensin type-la receptor gene knockout (At1a-/-) and wild-type (At1a+/+) mice. In At1a-/- mice, the levels of renal cortical eNOS mRNA and protein were 5 times and 3.5 times higher, respectively, in the high-salt (4% NaCl) group than in the low-salt group (0.3% NaCl). Systemic BP of the high-salt group (105 +/- 4.4 mmHg) was significantly higher than that of the low-salt group (77.0 +/- 4.7 mmHg). When hydralazine was administered to the mutant mice fed a high-salt diet, BP was reduced to 72.5 +/- 1.3 mmHg, with decreases in the levels of renal eNOS mRNA and protein expression to about half of those found in nontreated group. Consistent with the results for eNOS mRNA and protein expression, nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity and eNOS immunoreactivity localized in the endothelium of the renal vasculature changed parallel with the amount of salt intake. In contrast to mutant mice, At1a+/+ mice did not show any changes in renal eNOS expression during the manipulation of salt intake and/or hydralazine-induced hypotension. These results suggest that Atla receptor-mediated inputs play critical roles in maintaining renal vascular eNOS expression and activity during changes in salt-water balance and systemic BP.

DOI： 10.1097/01.ASN.0000130922.75125.B8

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARCEL DEKKER INC  

The aim of this study is to clarify the associations between diurnal blood pressure variation, physical activity and health-related quality of life (HRQOL). Ninety-seven volunteers, including 52 hypertensive patients and 45 healthy subjects (average age, 48 years) participated in this study. Twenty-four hour ambulatory blood pressure and heart rate variability were measured using TM2425 (A&D Co). Physical activity was measured using actigraphy, and HRQOL was assessed by a Medical Outcome Study Short-Forum 36-Item Health Survey (SF-36). Awake mean physical activity positively correlated with the nocturnal dip in systolic blood pressure (SBP) (r = 0.242, p &lt; 0.02) and diastolic blood pressure (DBP) (r = 0.219, p &lt; 0.04). The score of physical functioning positively correlated with awake mean physical activity (r = 0.265, p &lt; 0.02). The score of role-emotional also correlated with awake mean physical activity (r = 0.269, p = 0.01). Using multiple regression analysis, the nocturnal dip in SBP was found to be correlated with awake and sleep mean physical activities (p &lt; 0.05, p &lt; 0.05, respectively). In conclusion, physical activity is associated with the nocturnal dip in blood pressure. Moreover, physical activity correlates with some of the factors of HRQOL.

DOI： 10.1081/CEH-120028553

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Language：Japanese   Publishing type：Research paper (scientific journal)  

Objective: The effects of long-term acting dihydropyridine calcium antagonists on daytime blood pressure (BP) changes and autonomic nervous activity have not been fully evaluated in patients with essential hypertension (EH). We assessed the changes in 24-h BP and position-related BP during daytime induced by benidipine in EH patients by using ambulatory BP monitoring (ABPM) devices equipped with a body-position sensor. Research design and methods: Nineteen patients with EH had ABPM before and after treatment with benidipine. Simultaneously, power spectral analysis of the heart rate was performed to calculate the high frequency (HF) components and low frequency (LF)/ HF component ratios as indices of the vagal and sympathovagal balances, respectively. Results: Benidipine significantly decreased 24-h, daytime, and sleeping BP in the EH patients (p&lt
0.01) from 150±13/86±9 to 142±12/79±8 (systolic BP/diastolic BP) mmHg, from 154±11/88±8 to 146±12/81±8 mmHg, and from 141±20/80±12 to 127±15/71±9mmHg, respectively. Benidipine also decreased BP during 3-h post-awakening period. After benidipine treatment, the standing and non-standing BP significantly and proportionally decreased (p&lt
0.05) from 156±14/90±8 to 150±13/ 83±8 mmHg and from 153±13/87±11 to 145±13/ 80±9 mmHg, respectively. Heart rates were not altered in both phases by treatment of benidipine. Benidipine did not change the HF components and LF/HF ratios between standing and non-standing periods (p&gt
0.05). Conclusions: During daytime periods, benidipine decreased BP both standing and non-standing without affecting autonomic nervous activity. Benidipine may be a potent antihypertensive agent to reduce BP without inducing reflex tachycardia.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

Several protein kinase C (PKC) isoforms may play important roles in cellular signaling pathways. Recent reports have suggested that PKC plays critical isoform-specific roles in the development of cardiac hypertrophy and heart failure. The purpose of the present study was to examine the expression profiles of PKC isoforms in models of cardiac hypertrophy and heart failure. We examined the cardiac expression of individual PKC isoforms at the cardiac hypertrophy stage and the heart failure stage in Dahl salt-sensitive rats by Western blot analysis. The levels of all PKC isoforms increased at the cardiac hypertrophy stage and the heart failure stage, but the pattern of increase differed among PKC isoforms at the heart failure stage. The expressions of PKCalpha, beta, and delta increased at the cardiac hypertrophy stage and remained elevated at the heart failure stage. On the other hand, the expression of PKCepsilon and atypical PKCs (aPKCs) increased at the cardiac hypertrophy stage, but this increase tended to decline at the congestive heart failure stage. These results suggest that there are two groups of PKC isoforms. Several reports have shown that PKCalpha, beta, and delta are involved in the development of cardiac hypertrophy and heart failure, and that PKCepsilon plays a role in the physiological hypertrophic responses and cardioprotective actions. These facts suggest that all PKC isoforms (PKCalpha, beta, delta, epsilon, and aPKCs) expressed in the heart may have similar functions at the cardiac hypertrophy stage, but that two groups of PKC isoforms (PKCalpha, beta, delta, and PKCepsilon, aPKCs) have different functions at the congestive heart failure stage.

DOI： 10.1291/hypres.26.421

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

Several protein kinase C (PKC) isoforms may play important roles in cellular signaling pathways. Recent reports have suggested that PKC plays critical isoform-specific roles in the development of cardiac hypertrophy and heart failure. The purpose of the present study was to examine the expression profiles of PKC isoforms in models of cardiac hypertrophy and heart failure. We examined the cardiac expression of individual PKC isoforms at the cardiac hypertrophy stage and the heart failure stage in Dahl salt-sensitive rats by Western blot analysis. The levels of all PKC isoforms increased at the cardiac hypertrophy stage and the heart failure stage, but the pattern of increase differed among PKC isoforms at the heart failure stage. The expressions of PKCalpha, beta, and delta increased at the cardiac hypertrophy stage and remained elevated at the heart failure stage. On the other hand, the expression of PKCepsilon and atypical PKCs (aPKCs) increased at the cardiac hypertrophy stage, but this increase tended to decline at the congestive heart failure stage. These results suggest that there are two groups of PKC isoforms. Several reports have shown that PKCalpha, beta, and delta are involved in the development of cardiac hypertrophy and heart failure, and that PKCepsilon plays a role in the physiological hypertrophic responses and cardioprotective actions. These facts suggest that all PKC isoforms (PKCalpha, beta, delta, epsilon, and aPKCs) expressed in the heart may have similar functions at the cardiac hypertrophy stage, but that two groups of PKC isoforms (PKCalpha, beta, delta, and PKCepsilon, aPKCs) have different functions at the congestive heart failure stage.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

In cultured vascular smooth muscle cells (VSMCs), interieukin-1beta (IL-1beta) stimulates inducible nitric oxide synthase (NOS) expression and nitric oxide (NO) production. IL-1beta also activates phospholipase A(2) (PLA(2)), and induces lipoxygenase (LOX) and cyclooxygenase-2 (COX-2). The present study investigated whether these metabolites are involved in the regulation of IL-1beta-induced NO production and NOS expression. Pretreatment with ONO-RS-082, the secretory PLA(2) (sPLA(2)) inhibitor, at 1 to 10 mumol/l reduced IL-1beta-stimulated nitrite production and NOS expression. Nordihydroguaiaretic acid (NDGA, 1 to 10 mumnol/l), the LOX inhibitor, also reduced IL-1beta (10 ng/ml)-stimulated nitrite production and iNOS expression in a dose-dependent manner. Exogenous 12(S)-hydroxyeicosatetraenoic acids (HETE) enhanced the IL-1beta-stimulated nitrite production and iNOS expression. On the other hand, the COX inhibitors, indomethacin and NS-398, had little effect on nitrite production or NOS expression. These results suggest that LOX products play important roles in the regulation of stimulus-induced NO production in VSMCs.

DOI： 10.1291/hypres.26.177

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

Among the consequences of the increasing prolongation of lifespan is a worldwide increase in the number of cases of dementia or impaired cognition. In the present study, to test the hypothesis that mechanisms independent of high blood pressure are involved in maintaining cognitive function, we assessed the effects of long-term dilazep treatment on cognitive dysfunction in normotensive Dahl salt-sensitive (Dahl S) rats fed a low-salt diet, using the standard passive avoidance test. Normotensive Dahl S rats fed a 0.3% NaCl diet were treated for 6 months with low-dose dilazep (2.5 mug/ml in drinking water) or high-dose dilazep (12.5 mug/ml). Systolic blood pressure was within normotensive range throughout the study and did not differ among the experimental groups. The results of the passive avoidance test revealed that dilazep treatment attenuated the decline of latency time relative to that in the untreated control rats (control latency time, 235 s; low-dilazep group, 389 s; high-dilazep group, 397 s), suggesting that the cognitive function of normotensive Dahl S rats was improved by dilazep treatment. This improvement of cognition was associated with significant increases in the number of neuronal cells in the hippocampal region and with an increase in capillary length in dilazep-treated Dahl rats. In addition, the dilazep treatments significantly attenuated arteriolar injury of glomeruli in the kidney. These data suggest that dilazep treatment, through vascular and non-vascular effects, maintains the brain function in Dahl S rats susceptible to vascular injury and organ dysfunction.

DOI： 10.1291/hypres.26.185

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：MEDIMOND S R L  

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Background. Diabetic patients with moderate to advanced renal failure have severe hypertension and often require multiple antihypertensive agents to control it. Nevertheless, no standardized therapy has been established. This study was designed to examine the safety and efficacy of the biliary-excreted angiotensin converting enzyme inhibitor temocapril in those patients whose blood pressure was not adequately decreased by calcium channel blocker monotherapy. Methods. Twenty-seven patients who did not reach the therapeutic goal of blood pressure (140/90 mm Hg) with amlodipine monotherapy were assigned to receive temocapril (2mg) and amlodipine (5mg) for 3 months. Blood samples for hematological and biochemical examinations were taken every month during treatment. Twenty-fourhour urine was collected to measure urinary protein excretion. Trough plasma concentrations and pharmacokinetics were measured during temocapril treatment. Results. Blood pressure was significantly decreased (P &lt
0.05) from 158 ± 14/91 ± 9 to 148 ± 15/83 ± 8mmHg by the addition of temocapril. The peak serum concentration (Cmax) was 86.3 ± 22.7 μg/l at 3.9 ± 1.6 h (Tmax) after administration. Mean area under curve for 0 to 24h (AUC0-24h) was 1179 ± 273 μg/l·h. Trough levels showed a steady state. After temocapril therapy, the slope of the reciprocal of creatinine decreased compared with that before the addition of temocapril. Urinary protein excretion significantly decreased from 3100 ± 1100 to 2300 ± 1100mg/day. There was no significant change in hematological and biochemical data. Conclusions. The present findings suggest that temocapril can be safely used in patients with advanced diabetic nephropathy, and in combination with dihydropyridine calcium channel blockers it decreases blood pressure and effectively retards the aggravation of renal insufficiency for 3 months in those patients.

DOI： 10.1007/s101570200039

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Language：Japanese   Publisher：(一社)日本臨床化学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Background/Aims: We investigated basal levels of serum and urinary lipocalin-type prostaglandin D synthase/beta-trace (L-PGDS) in type-2 diabetic patients and explored whether glycemic control affects L-PGDS status in another 55 diabetic inpatients with normoalbuminuria. Methods: Fifty-five type-2 diabetic outpatients (HbA1c, 9.14 +/- 0.20%; creatinine (Cr), 85.1 +/- 2.4 mumol/l), and 55 age-matched healthy control subjects were recruited. Serum and urinary levels of L-PGDS were determined with respect to the stage of diabetic nephropathy. The L-PGDS was localized by immunohistochemistry. Results: The urinary L-PGDS index increased in diabetic patients, compared with the controls (234.8 +/- 27.4 vs. 73.8 +/- 7.8 mug/mmol Cr, p &lt; 0.001). Even in normoalbuminuric patients as well as in microalbuminuric patients, urinary L-PGDS indexes were higher than the controls (166.0 +/- 21.1, p &lt; 0.0001 and 338.6 +/- 62.5 mug/mmol Cr, p &lt; 0.0001, respectively), although the serum L-PGDS level was equal to that in the control subjects. Multiple regression analysis revealed that the urinary L-PGDS index was predicted solely by glucose levels and type-IV collagen index, whereas the serum L-PGDS was determined mainly by age and serum Cr. Glycemic control reduced the urinary L-PGDS index towards the normal range in diabetic patients with normoalbuminuria (172.3 +/- 6.6 vs. 118.1 +/- 2.6 (SE) mug/mmol Cr, p &lt; 0.0001). Immunohistochemistry showed that L-PGDS was uniquely present in the renal tubules in diabetes while in nondiabetics, L-PGDS occurred solely in the peritubular interstitium, not in the tubular cells. Conclusion: Inadequate glycemic control is responsible for urinary L-PGDS excretion in the diabetic patients. Urinary L-PGDS is useful to predict subclinical renal injury associated with type-2 diabetes. Copyright (C) 2002 S. Karger AG, Basel.

DOI： 10.1159/000064473

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Language：Japanese   Publisher：(一社)日本臨床化学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Lipocalin-type prostaglandin D synthase (L-PGDS) reportedly well predicts cardiovascular injuries in humans. However, little is known about the implications of L-PGDS in hypertension. In the present study, we investigated the alterations of serum and urinary L-PGDS in hypertensive patients with or without renal dysfunction. A total of 111 patients with hypertension (EHT; 65 with normoalbuminuria, 23 with microalbuminuria, 12 with macroalbuminuria, 11 with renal failure) and 102 normotensive, nomoalbuminuric subjects (NT) were studied. L-PGDS was measured by enzyme-linked inummosorbent assay, and L-PGDS in the kidney was localized using immunohistochemical methods. Blood pressure was higher in EHT groups than in the NT group (P&lt;0.0001). There were no differences in age, gender, BMI, TC, TG, and HbAlc levels among the groups. Serum creatinine and urinary albumin levels were higher in the group with renal failure. Serum levels of L-PGDS were increased in EHT with normoalbuminuria, as compared with NT (0.88+/-0.05 versus 0.65+/-0.02 mug/mL; P&lt;0.001). Serum levels of L-PGDS increased with the renal function worsened and positively correlated with serum creatinine, particularly in patients with renal impairments (r=0.76, P&lt;0.0001). Similarly, the urinary L-PGDS excretions in EHT with normoalbuminuria were higher than that in NT (2.31&PLUSMN;0.29 versus 1.16&PLUSMN;0.14 mg/gCr, P&LT;0.001), whereas there were no differences in urinary albumin excretion between the 2 groups. Moreover, urinary L-PGDS excretion increased dramatically with an increase in albuminuria or proteinuria. L-PGDS was stained in the tubules and the interstitium of the kidney in nephrosclerosis. In conclusion, patients with hypertension exhibited a higher level of L-PGDS in serum and urine, and this became increasingly obvious along, with advance in renal dysfunction. These data suggest that L-PGDS metabolism is related to blood pressure and kidney injuries associated with hypertension.

DOI： 10.1161/hy0202.102835

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A 31-year-old woman was diagnosed as having Bartter's syndrome in 1978, although suspicions remained that she had been taking diuretics surreptitiously. Careful observation and repeated urinary drug analyses revealed no clue that she had been taking diuretics, until 20 years later, when the urine samples at last disclosed traces of furosemide. At this time she showed proteinuria, of 2 g/day, and hypercholesteremia. The glomerular filtration rate had decreased to 66 ml/min per 1.73m2. The 24-h urinary concentrations of β2-microglobulin, N-acetyl-β-D-glucosaminidase (NAG) activity, and other urinary enzymes that are indicators of damage in proximal tubular cells, were increased, showing proximal tubular damage. The function of the loop of Henle was evaluated by a hypotonic saline loading test. The fractional distal chloride reabsorption, an index of the solute conservation rate in the loop of Henle, was 65.4%, which was lower than the normal value (88.9 ± 6.2%). The maximal urinary concentrating ability was 357 mOsm/kg·H2O, and a short ammonium chloride loading test showed impairment in the acidification of the urine. The third renal biopsy specimens showed some obsolescent glomeruli, marked juxtaglomerular cell hyperplasia, intraluminal calcification, interstitial infiltration of lymphocytes with fibrosis, and thickening of arteriolar walls with narrow lumens. Patients often attempt to hide their use of diuretics from medical staff, leading to them to make a misdiagnosis of Bartter's syndrome. Although the patient described here has not experienced life-threatening adverse effects from furosemide abuse, some findings appear to be irreversible, suggesting the deterioration of renal function. Patients should realize that longstanding abuse of diuretics causes not only metabolic abnormalities but also the risk of renal damage. © 2002 Japanese Society of Nephrology.

DOI： 10.1007/s101570200010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Objective: Circulating levels of lipocalin-type prostaglandin D synthase (L-PGDS)/beta -trace reportedly increase in renal failure as well as in cardiovascular injuries. We investigated the alterations of L-PGDS in urine and plasma in the early stage of type-2 diabetic patients. Method: Thirty-six type-2 diabetic patients and 29 normal subjects were studied. Overnight spot urine and plasma samples were obtained in the morning. L-PGDS was measured by ELISA method using anti-L-PGDS antibody. Variables indicating renal function were determined. Results: Plasma L-PGDS concentration was slightly higher in the patients with diabetes mellitus than in the control subjects, whereas the urinary L-PGDS excretion almost doubled in the diabetic patients as compared with that in the control subjects. Plasma L-PGDS was determined by plasma creatinine (Cr) concentration while urinary L-PGDS excretion was correlated solely with urinary protein excretion. There was no relationship between plasma L-PGDS concentration and urinary L-PGDS excretion. The averaged plasma concentration of L-PGDS in the diabetics with a normal Cr level ill plasma, corresponding to that in the controls, was determined by the plasma Cr concentration. On the other hand, the urinary L-PGDS excretion was determined by the amount of proteinuria and greater in the diabetics with a normal Cr level in plasma than in the controls even when the patients exhibited urinary protein excretion equal to that in the control subjects. Conclusions: Urinary L-PGDS excretion increased in the early stage of kidney injury in patients with type-2 diabetes mellitus. The urinary excretion was correlated independently with urinary protein excretion even when there was no difference in urinary protein or albumin excretions, thereby suggesting that urinary L-PGDS excretion is possibly a more sensitive indicator of renal injuries than proteinuria. Urinary L-PGDS may thus predict the progression of renal injuries in diabetic patients. Copyright (C) 2001 S. Karger AG. Basel.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The Dahl salt-sensitive (DS) rat, a genetic model of salt-induced hypertension in humans, is more likely to develop severe vascular injuries than a rat with spontaneous hypertension. We designed an experiment: to scrutinize the effects of renin-angiotensin inhibition on cognitive dysfunction in the aged, normotensive DS with a passive avoidance test. Eighteen months of treatment with a very low dose of the angiotensin-converting enzyme (ACE) inhibitor cilazapril (2.5 mu g/mL in drinking water) or the angiotensin II type 1 receptor antagonist E4177 did not reduce blood pressure throughout the experiment, although in the low dose cilazapril group (12.5 mu g/mL in drinking water), blood pressure dropped within 6 months after treatment began. The cilazapril treatments dose-dependently improved memory function in the aged, normotensive DS fed a low-salt diet compared with the untreated, control rats. This improvement was associated with significant increases in hippocampal CA1 cells and capillary densities in the CAL regions compared with those in the untreated DS, Similarly, E4177 slightly improved the memory dysfunction observed in the aged DS. The cells in the hippocampal CA1 region were restored slightly, but the capillary densities were not influenced by the receptor antagonist. On the other hand, the ACE inhibitor and receptor antagonist both attenuated urinary protein excretions with an improvement of glomerular sclerosis. These data suggest that long-term treatment with an ACE inhibitor improves memory dysfunction probably through restoration of capillary and hippocampal cells. The effects are due to the inhibition of the angiotensin II type 1 receptor and probably to the enhancement of the kallikrein-kinin system.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Objective We recently reported that the renin-angiotensin system plays an important role in the progression of vascular and kidney injuries, even in Dahl salt-sensitive rats with volume-dependent hypertension. In this study, we investigated whether a high-salt diet increases susceptibility to kidney injury induced by angiotensin II in normotensive, uni-nephrectomized Sprague-Dawley rats, which mimics the condition of salt-volume repletion and blunted renin-angiotensin system.
Methods The rats were fed either a low-salt (0.3% NaCl) or a high-salt (4% NaCl) diet and divided into five groups: two control groups with a low-salt or a high-salt diet without angiotensin II infusion (saline infusion), and three angiotensin II groups (angiotensin II infusion, 10 or 50 ng/ kg per min with high-salt diet, 50 ng/kg per min with low-salt diet, subcutaneously). The rats were kept on these regimes for 8 weeks. The blood pressure was measured every week Functional and morphological alterations in the kidney were assessed at the end of the experiment.
Results There were no differences in the arterial blood pressures of the five experimental groups. However, angiotensin II infusion increased the weights of the heart and aortic walls in a dose-dependent manner in the high-salt groups. There was also a dose-dependent increase in proteinuria, N-acetyl-beta-D-glucosaminidase activity (NAG) excretion, and additional glomerular and arterial injuries in the kidney, associated with angiotensin II infusion in the high-salt groups. In the rats given a higher dose of angiotensin II, the high-salt diet significantly increased the weights of the heart and aortic walls and exacerbated the renal function and morphological injuries, compared to the low-salt group. High-salt diet alone increased the kidney and heart weights. However, it did not significantly influence the results of the morphological and functional study. On the other hand, angiotensin II infusion on a low-salt diet showed a trend towards glomerular damage; however, the effects were small and not significant. Similarly, there were few effects of angiotensin Il infusion on morphology and functional study on a low-salt diet.
Conclusion These data clearly show that a high-salt intake increases susceptibility of the kidney to injuries induced by low doses of angiotensin II in normotensive, uninephrectomized rats. J Hypertens 1999, 17:923-932 (C) Lippincott Williams & Wilkins.

DOI： 10.1097/00004872-199917070-00008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：KARGER  

Aims: We investigated whether kallikrein infusion attenuates renal injury in Dahl salt-sensitive rats with hypertension and assessed the role of bradykinin-nitric oxide axis in the renal protection using HOE-140, the bradykinin type-2 (B-2) receptor specific antagonist. Methods: Subdepressor dose of purified rat urinary kallikrein (RUK) (400 ng/day) was continuously infused through the jugular vein by an osmotic mini-pump for 4 weeks in Dahl salt-sensitive (Dahl S) rats fed a high-salt (2% NaCl) diet. Results: Blood pressure increased in a time-dependent manner in Dahl S rats fed a high-salt diet. The RUK infusion did not influence the elevation of blood pressure in Dahl S rats. However, the RUK infusion significantly decreased urinary protein excretion, and increased glomerular filtration rate, as compared with untreated high-salt Dahl S rats. Morphological investigation disclosed that the RUK infusion significantly attenuated glomerulosclerosis and arterial and tubular injuries in the kidney of hypertensive Dahl S rats. The RUK infusion produced an increase in urinary excretions of nitric oxide and cyclic guanosine monophosphate. In addition, the RUK infusion enhanced the generation of nitric oxide from the kidney slices. The functional and morphological effects of the RUK infusion on the kidney were completely lessened by co-administration of the bradykinin B-2-receptor antagonist, HOE-140. Conclusion: Long-term infusion of subdepressor close of rat urinary kallikrein attenuates functionally and morphologically the progression of renal injury in Dahl rats susceptible to salt-induced hypertension, and that the protection is mediated by stimulation of bradykinin B-2 receptor.

DOI： 10.1159/000045275

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether treatment with an angiotensin II (ANGII) subtype-l receptor antagonist delays the onset of NIDDM and attenuates diabetic nephropathy in the OLETF rat. OLETF rats fed a regular chow were treated with ANGII subtype-l receptor antagonists (E4177 or TA606) for 22 weeks. Hemodynamic changes, glucose metabolism, and the effects on diabetic nephropathy were examined. Systolic blood pressure increased in OLETF rats in an age-dependent manner. OLETF rats exhibited increases in plasma concentrations of glucose and insulin and developed glucosuria at the age of 28 weeks. The changes in glucose metabolism were associated with proteinuria and an increase in urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG). Morphologic investigation revealed nodular lesions in glomeruli in the OLETF rats. The ANGII receptor antagonist treatment abolished the blood pressure elevation. However, the treatment did not affect plasma glucose and insulin levels and did not significantly reduce glucosuria. Nodular lesions in glomeruli were not improved by the treatment. However, the receptor antagonists significantly reduced proteinuria and urinary NAG excretion. Multivariate analyses revealed that proteinuria was determined by systolic blood pressure, lipid metabolism, and glucose levels in plasma. ANGII subtype-l antagonism does not improve glucose metabolism in the OLETF rat model of NIDDM, which has abnormalities in the glucose-uptake system. Blood pressure elevation and part of the proteinuria associated with NIDDM depends on the renin-angiotensin system rather than glucose metabolisms per se. (C) 1999 American Journal of Hypertension, Ltd.

DOI： 10.1016/S0895-7061(98)00276-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

To assess the effects of sodium reduction on insulin sensitivity in hypertension, we examined the change of insulin sensitivity after two degrees of dietary sodium restriction by the euglycemic hyperinsulinemic glucose clamp method in 12 subjects with primary hypertension. A controlled period of 1 week, when the subjects were taking a normal sodium diet was followed by a randomized crossover study in which the subjects were placed on either moderate or strict reduced sodium diets for 1 week. The result of the 1-week moderate dietary sodium reduction from 200 to 100 mmol/day showed significant decreases in systolic and diastolic blood pressure by 6.5 and 5.0 mm Hg, respectively. Strict dietary sodium reduction to 30 mmol/day for 1 week resulted in no further decrease in blood pressure, but it increased plasma insulin by 40.6% without changing plasma glucose. There were no changes in glucose infusion rate (GIR) or insulin sensitivity index (ISI), which is a measure of GIR divided by plasma insulin, after moderate dietary sodium reduction. However, strict dietary sodium reduction induced decreases in GIR by 19.8% (from 1318 +/- 189 to 1057 +/- 173 mu mol/m(2)/min; P &lt; .01), and ISI by 20.5% (from 16.6 +/- 2.1 to 13.2 +/- 1.9 mu mol/m(2)/min/mu U/mL; P &lt; .01) with a paralleled increase of plasma norepinephrine by 90.0% (from 150.5 +/- 61.6 to 287.3 +/- 114.9 pg/mL; P &lt; .01). These results indicate that dietary sodium restriction leads to a deterioration of insulin sensitivity when plasma norepinephrine levels increase, and suggest that moderate dietary sodium reduction may lower blood pressure without a distinct adverse effect on glucose metabolism in subjects with primary hypertension. Am J Hypertens 1998;11:1048-1055 (C) 1998 American Journal of: Hypertension, Ltd.

DOI： 10.1016/S0895-7061(98)00126-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Heart Journal Association  

This study compared renal and intestinal handling of sodium in Dahl-Iwai salt-sensitive (S) and salt-resistant (R) rats given a normal-salt diet (0.3% NaCl) and a high-salt diet (4.0% NaCl). Six-week-old female S and R rats (n = 7 each) were given a normal-salt diet for 14 days followed by a high-salt diet for 3 weeks. Systolic blood pressure was significantly higher in the S rats than in the R rats only at the end of the high-salt diet period (170 ± 5, mean ± SEM, vs 152 ± 1 mmHg, P &lt
0.01). Daily sodium intake, water intake, urine volume, and urinary and fecal excretions did not significantly differ between the R and the S rats during the normal- and high-salt diets, except for a slight, although significant, decrease in fecal sodium excretion in the S rats as compared with the R rats in the 2nd week of the high-salt diet period. After switching from the normal-salt diet to the high-salt diet, urinary sodium excretion increased by 17- to 18-fold and fecal sodium excretion increased by about 5-fold in the 1st week of salt loading. The changes in urinary and fecal sodium excretions did not differ significantly betweeen the groups. Cumulative sodium retention was similar in the two groups. The aldosterone/creatinine ratio in 24-hr urine, which was significantly lower in the S than in the R rats during the normal-salt diet, decreased to similar levels in both groups after salt loading, indicating a blunted response of aldosterone in the S rats. Thus, there were no discernible differences in renal and intestinal handling of sodium between the S and the R rats, except for a slight-, but significant, difference in fecal sodium excretion in the 2nd week of the high-salt period. The results indicate that inappropriate suppression of aldosterone or some other mechanism induced by salt loading may be involved in blood pressure elevation in Dahl-Iwai S rats.

DOI： 10.1536/ihj.39.109

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Churchill Livingstone Inc.  

Background: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is a new genetic model of non-insulin-dependent diabetes mellitus (NIDDM). We investigated whether angiotensin inhibition influences the onset of NIDDM and brings about a regression of renal injury in diabetes mellitus. Methods and Results: Six-week-old OLETF rats were treated with the angiotensin-converting enzyme (ACE) inhibitors imidapril or enalapril for 16 weeks. Systolic blood pressure is increased in an age-dependent manner in OLETF rats. In this study, the elevation in systolic blood pressure was dose-dependently reduced by ACE inhibitor treatment. In OLETF rats, plasma concentrations of insulin and glucose increased and the glucosuria occurred at the age of 22 weeks. Simultaneously, OLETF rats exhibited proteinuria and nodular lesions in glomeruli. The ACE inhibitor treatment almost completely reduced glucosuria, and also decreased plasma concentrations of insulin and glucose in OLETF rats. ACE inhibitor treatment lessened the proteinuria and attenuated morphologically the severity of nodular lesions in OLETF rats. Moreover, increases in plasminogen activator inhibitor 1 (PAI-1) in OLETF rats were reduced by the ACE inhibitor treatment, and the improvement of glomerular lesions was related to decreases of PAI-1 and angiotensin II levels in plasma but not to improvement of glucose metabolism. Conclusions: ACE inhibitors delay onset of NIDDM with attenuation of kidney injury. The regression of kidney lesions is probably due to angiotensin reduction but not to glucose metabolism per se. ACE inhibitor drug therapy may be useful in preventing NIDDM and the subsequent renal injury in patients with NIDDM.

DOI： 10.1177/107424849800300408

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Angiotensin II (Ang II) progresses to remodeling of the cardiovascular system through nonhemodynamic as well as hemodynamic effects. There have been few data in vivo on whether subpressor concentration of Ang II is exerted to injure directly the cardiovascular system in hypertension. To test this hypothesis, we investigated, using Dahl salt-sensitive (Dahl S) rats, whether subpressor dose of Ang II progresses to cardiovascular injury observed in salt-induced hypertension. Recent studies have provided evidence that renin-angiotensin inhibition protects against renovascular injury in human hypertension as well as in experimental animals. Particularly in the case of Dahl salt-sensitive rats, a genetic model of volume-dependent hypertension in humans, they are likely to develop more severe arterial and renal injuries than those seen in spontaneously hypertensive rats with similar blood pressure levels. The mechanism of the susceptibility to hypertensive injuries is uncertain; however, renin-angiotensin inhibition significantly improved morphologic and functional injuries in the kidney of Dahl S rats. Conversely, subpressor dose of Ang II infusion exacerbated renal function and progressed to glomerulosclerotic lesions. Alterations of Ang II concentration in physiologic range influenced morphologic and functional injuries in Dahl S rats. Multivariate analysis revealed that activity of the renin-angiotensin system is an independent risk factor to glomerular injury in salt-induced hypertension. These data are in favor of the therapeutic strategy in human hypertension that inhibition of renin-angiotensin system is of value to produce beneficial effects of blood pressure reduction on organ injuries. (C) 1997 American Journal of Hyyertension, Ltd.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats. A subdepressor dose of purified rat urinary kallikrein (RUK) (700 ng/day) was infused intravenously by an osmotic minipump for 4 weeks in male Dahl S rats fed a high-salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure. However, urinary protein excretion was significantly decreased, and the glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of the glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl S rats. The kallikrein infusion increased the urinary excretion of bradykinin and stimulated the excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by the RUK infusion. The alterations induced by such infusion were potentiated by the concomitant administration of the angiotensin converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl S rats, and this is probably mediated by an enhanced function of the kallikrein-kinin-prostaglandin and nitric oxide systems. (C) 1997 American Journal of Hypertension, Ltd.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

We investigated the influence of the vascular and renal thromboxane system on the antihypertensive effects of the alpha(1) adrenoceptor antagonist (alpha(1) blocker) bunazosin in spontaneously hypertensive rats (SHR). SHR were treated for 2 weeks with the alpha(1) blocker bunazosin (0.5 mg/kg body weight/day). The systolic blood pressure immediately declined with bunazosin treatment, and then rose toward the level observed in untreated SHR. This antihypertensive effect was accompanied by a decrease in the ratio of prostacyclin to thromboxane A(2) in the vascular wall and the kidney. A subdepressor dose of the thromboxane synthase inhibitor OKY-046 lessened the thromboxane generation during bunazosin treatment, and synergistically potentiated the antihypertensive action of the alpha(1) blocker. Such synergy was also observed between OKY-046 and prazosin, an alternative alpha(1) blocker, but not with amosulalol, an alpha(1) blocker having no quinazoline moiety. alpha(1) blockers with a quinazoline moiety dose-dependently stimulate thromboxane generation in cultured smooth muscle cells from SHR. These data indicate that alpha(1) blockers enhance thromboxane generation in the arterial wail and kidney, thereby contributing to the lessening of the antihypertensive effects observed during alpha(1) blocker treatment.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Hypertension  

Serum N-acetyl-β-D-glucosaminidase activity (NAG) is a possible predictor of vascular injury in hypertension. We assessed whether the activity of this enzyme reflects vascular damage in a genetic rat model of non-insulin-dependent diabetes mellitus (NIDDM) in humans. Otsuka Long-Evans Tokushima Fatty (OLETF) rats fed a regular chow were treated with the angiotensin converting enzyme (ACE) inhibitor imidapril for 16 wk. Systolic blood pressure increased in a time-dependent manner in the untreated OLETF rats as compared with that in the control Long-Evans Tokushima (LET) rats. The blood pressure elevation was associated with increases in cardiac and aortic weight. Imidapril treatment significantly attenuated the blood pressure elevation and reduced the increases in cardiac and aortic weight. The untreated OLETF rats had higher plasma glucose and insulin concentrations than did the LET rats and presented with glucosuria at the age of 22 wk. Imidapril treatment strikingly decreased plasma glucose levels and the glucosuria. Plasma insulin concentrations decreased, approaching those of the non-diabetic control LET rats. ACE inhibitor treatment attenuated the nodular lesions in the glomeruli of OLETF rats and improved the kidney function. Serum NAG activity increased significantly by 35% in the untreated rats
this increase was attenuated significantly by imidapril treatment. The reduction in serum NAG activity correlated with improvement in cardiovascular injury. In contrast, there were no changes in urinary NAG excretion in the three OLETF rat groups. In addition, NAG excretion did not correlate with indices of cardiovascular injury. These data suggest that serum NAG activity is useful in predicting injury in the cardiovascular system in rats with diabetes mellitus.

DOI： 10.1291/hypres.20.193

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Hypertension  

We investigated the effects of the immunosuppressant HR-325 on arterial lesions in Dahl rats with salt-induced hypertension. Forty-eight 6-wk-old Dahl salt-sensitive (DS) rats were divided into 1) a low-salt (0.3% NaCl) group, 2) a high-salt (4% NaCl) group, 3) a high-salt and low-dose (1 mg/kg) HR-325 group, and 4) a high-salt and high-dose (30 mg/kg) HR-325 group. The rats were treated for 8 wk. Various variables of renal function and morphological alterations in the kidney were assessed. Blood pressure was measured by the tail-cuff method. HR-325 significantly decreased systolic blood pressure in a dose-dependent manner throughout the study. HR-325 tended to decrease plasma creatinine level and increase creatinine clearance rate. Morphological studies revealed that HR-325 treatment strikingly resolved infiltration of immune-related cells in perivascular and intraluminal lesions, thereby decreasing the total arterial injury score by 32%. High-dose HR-325 also attenuated glomerulosclerosis and tubular injury by 35% and 34%, respectively, as compared with untreated high-salt Dahl S rats. Reduced levels of immune-related cells resulted in a decrease in urinary nitrite excretion. These data indicate that long-term treatment with the immunosuppressant HR-325 decreases systolic blood pressure in Dahl salt-sensitive rats, and that this decrease is associated particularly with resolution of infiltration of immune-related cells in arterial lesions. Hyperimmune state is responsible in part for the susceptibility of Dahl S rats to hypertensive organ damage.

DOI： 10.1291/hypres.20.91

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa Healthcare  

We investigated the role of lipid metabolism in renal protection by chronic cicletanine treatment in Dahl salt-sensitive (Dahl S) rats with salt- induced hypertension. Forty four 6-week old Dahl S rats were divided into four groups: (1) low-salt (0.3% NaCl) control group
(2) high-salt (4% NaCl) control group
(3) low-dose (10 mg/kg/day) cicletanine (CICL)-treated group given a high-salt diet
and (4) high-dose (30 mg/kg/day) cicletanine-treated group given a high-salt diet. The rats were treated for 6 weeks
blood pressure was measured by the tail-cuff method. Cicletanine significantly reduced the systolic blood pressure in a dose-dependent manner (223 mmHg in the high-salt controls vs 195 mmHg in the high-dose, high-salt group, p &lt
0.01). Cicletanine treatment did not affect plasma concentration of total cholesterol or triglyceride or free fatty acid: in contrast, it significantly decreased low-density lipoprotein (LDL) cholesterol and increased high- density lipoprotein (HDL) cholesterol. Morphological examination demonstrated that glomerulosclerosis in the kidney was significantly improved by 15% with high-dose cicletanine (p &lt
0.01). Multivariate analysis revealed thai glomerular sclerosis was determined independently by LDL cholesterol levels and arterial injury score, but not by total cholesterol or HDL cholesterol levels or blood pressures. LDL cholesterol was also an independent predictor of urinary excretion of protein. Thus, it is suggested that cicletanine treatment lowers the levels of LDL cholesterol in Dahl salt-sensitive rats, and that besides blood pressure reduction, this decrease in LDL cholesterol level contributes, in part, to regression of glomerular injury in salt- induced hypertension.

DOI： 10.3109/08037059709061935

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

We characterized the adenosine A(1) receptor and the levels of its mRNA expression in the ventricles of 6- and 13-wk-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The binding of 2-chloro-[H-3]cyclopentyladenosine ([H-3]CCPA), an A(1) agonist ligand, to ventricular membranes was saturable and reversible. The receptor density was significantly lower in SHR than in WKY at 13 wk. The dissociation constant values were not different among these groups. In Northern blot analysis using rat A(1) receptor cDNA, levels of mRNA did not differ significantly in the two groups at 13 wk, but the level in SHR significantly exceeded that in WKY at 6 wk. Because plasma adenosine levels were reported to be increased at 13 wk in SHR and we found mRNA levels were similar at this age, the discrepancy between A(1) receptor density and its mRNA levels might be related to the desensitization of A(1) receptors. Although the implication of this decreased density of A(1) receptors is not known, it may involve an increased susceptibility to ischemia.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

To assess the role of insulin resistance in obesity hypertension, we examined the change of insulin sensitivity after weight loss in 24 obese hypertensive subjects by the euglycemic hyperinsulinemic glucose clamp method. The results of the 4-week calorie-restricted diet were a weight loss of 10.2% (from 74+/-12 to 67+/-11 kg, P&lt;.01) and a decrease in mean blood pressure of 13.1% (from 124+/-7 to 107+/-9 mm Hg, P&lt;.01). A decrease in plasma norepinephrine (from 208+/-74 to 142+/-52 pg/mL, P&lt;.01) was associated with decreases in plasma renin activity (from 1.06+/-0.98 to 0.62+/-0.63 ng/mL per hour, P&lt;.01) and serum aldosterone (from 70+/-28 to 57+/-24 pg/mL, P&lt;.05). Glucose infusion rate increased significantly (42.9%), from 809+/-194 to 1155+/-251 mu mol/m(2) per minute. The insulin sensitivity index, which is a measure of the glucose infusion rate divided by plasma insulin, increased significantly (42.6%), from 10.8+/-3.5 to 15.4+/-4.4 (mu mol/m(2) per minute)/(mu U/mL). Stepwise multiple linear regression analysis showed that changes of plasma norepinephrine, insulin sensitivity index, plasma renin activity, and age were significant predictive factors for the change of mean blood pressure after weight loss. These results indicate a distinct relation between an improvement of insulin sensitivity and a decrease in blood pressure after weight loss in obese hypertensive subjects. The decrease in blood pressure after weight loss is probably related to the suppression of sympathetic nervous activity.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN CIRCULATION SOC  

We describe a rare case of ACE inhibitor-induced angioedema during long-term therapy in a 51-year-old male patient with essential hypertension; and this is the third case reported of this adverse reaction in Japan. The patient received enalapril for 66 months, and complained of a dry cough which was mild and tolerable. Recently, he noted tenderness of his mouth, face, swelling of lips and tongue for 3 to 4 h after taking his morning dose of enalapril. These symptoms abated spontaneously, so he continued taking the drugs. He again noted similar episodes of angioedema 29 days after the first experience. He had no further episodes of angioedema or dry cough after cessation of enalapril. This case of angioedema developed during long-term therapy with enalapril administered as 19,930 mg of enalapril maleate.
We emphasize that angioedema may occur at any time during the use of enalapril.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INST ADV RES ASIAN SCI & MED  

We investigated whether the Chinese herbal remedy, Hachimi-jio-gan extract, attenuates the renal injury seen in salt-induced hypertension in Dahl salt-sensitive (Dahl S) rats. Administration of this extract for 5 weeks dose-dependently decreased systolic blood pressure in Dahl S rats fed with a high-salt (2% NaCl) diet. This blood pressure reduction was associated with a decrease in cardiac mass and in thickness of the aortic wall. Urinary excretion of prostaglandin E(2) was increased and glomerular filtration rate was improved with this treatment. Glomerulosclerosis and arterial injury in the kidney were morphologically improved, These data suggest that Hachimi-jio-gan extract exhibits an antihypertensive effect, which is associated with partial resolution of renal injury in salt-induced hypertension.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Hypertension  

The effects of chronic cicletanine (CICL) treatment on endothelial cell function were investigated in Dahl salt-sensitive (Dahl S) rats. Forty-four six-week-old Dahl S rats were divided into four groups: i) 10 Dahl S rats fed a low-salt (0.3% NaCl) diet and given vehicle, ii) 12 Dahl S rats fed a high-salt (4% NaCl) diet and given vehicle, iii) 11 low dose (10 mg/kg body weight/d) CICL-treated Dahl S rats fed a high-salt diet, and iv) 11 high-dose (30 mg/kg body weight/d) CICL-treated Dahl S rats fed a high-salt diet. The rats were maintained on the respective salt regimen for 12 wk and treated with cicletanine for the last 6 wk, after which various parameters of endothelial cell function were determined. Systolic blood pressure, measured by the tail-cuff method, was reduced significantly by high-dose cicletanine (223 us. 195 mmHg, p &lt
0.01). Scanning electron microscopy revealed that high-dose CICL attenuated endothelial injury in the aorta of Dahl S rats. Arterial lesions in the heart and glomerulosclerosis in the kidney were significantly reduced by treatment with high-dose CICL. Moreover, prostacyclin (PGI2) and prostaglandin E2 (PGE2) generation in the aortic wall was significantly increased by 28% (p &lt
0.005) and by 149% (p &lt
0.001), respectively, by high-dose CICL. Nitric oxide (NO) generation in the aortic walls was significantly increased by high-dose CICL (0.38 us. 15.4 pmol/cm2/30 min, p &lt
0.001). This effect was accompanied by a 47% increase in cGMP synthesis in the vascular walls. In contrast, the synthesis of PGI2, PGE2, and NO in the kidney slices did not differ significantly among the four experimental groups. In addition, the generation of vasodilatory substances inversely correlated with the score of vascular lesions in the heart and kidney. The results suggested that the blood pressure reduction by chronic cicletanine treatment in Dahl S rats is associated with an improvement in endothelial cell function. The increased release of vasodilatory substances from endothelial cells may contribute to the blood pressure reduction and attenuation of vascular injury observed with cicletanine treatment.

DOI： 10.1291/hypres.19.263

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

We investigated the effects of the adenosine type-1 receptor antagonist FK-838 on salt-induced hypertension in Dahl-Sea salt-sensitive (Dahl S) rats. Dahl S rats fed a high-salt (4% NaCl) diet for 4 weeks were treated with FK-838 or hydrochlorothiazide for 4 weeks and alterations in kidney function and morphologic changes were assessed. FK-838 attenuated the development of hypertension in Dahl S rats, and caused a decrease in aortic weight in a dose dependent fashion. The adenosine antagonist did not produce any detectable metabolic disturbance. The blood pressure reduction by FK-838 was associated with attenuation of glomerular and arterial injury in the kidney. The renal protective effect of FK-838 treatment was associated with a reduction of plasma renin activity and plasma aldosterone concentration. In contrast, the thiazide diuretic, which produced almost the same blood pressure reduction as FK-838, did not attenuate renal damage. These data indicate that adenosine Al receptor antagonism reduces salt-induced hypertension and the consequent renal injuries.

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This study was designed to examine the effects of sex, age, and a high-salt diet on cardiac alpha(1)-adrenoceptors in an animal model of genetic hypertension, the Dahl salt-sensitive rat. Ventricular alpha(1)-adrenoceptors were measured by radioligand binding with [H-3]prazosin in membrane fractions in Dahl S and R rats of 7, 12, and 15 weeks of age.
In both S and R rats, the maximal binding (B-max) of alpha(1)-adrenoceptor binding was greater in male than in female rats. The B-max decreased with age in both the S and R strains; at 12 weeks of age, B-max was approximately one-half of that observed at 7 weeks of age in both S and R strains. In the rats fed a high-salt diet, the B-max tended to be greater in S rats than in R rats at 12 weeks of age and this difference became significant at 15 weeks of age. A significant positive correlation was found between the B-max and the heart-to-body weight ratio in the Dahl S and R rats. The dissociation constant (K-d) was not different between male S and R rats at each age. These results suggest that the ventricular alpha(1)-adrenoceptor may be involved in cardiac hypertrophy in Dahl rats.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：RAPID SCIENCE PUBLISHERS  

Objective: To investigate the effects of subpressor doses of angiotensin II (Ang II) on the progression of renal injuries in Dahl salt-sensitive (Dahl-S) rats with hypertension.
Methods: Rats were fed a high-salt (4% NaCl) diet and given an Ang II infusion (10 or 50 ng/kg per min, subcutaneously) for 4 weeks.
Results: The plasma Ang II concentration achieved in the high-dose Ang II infusion was lower than that in low-salt (0.3% NaCl) normotensive rats. The Ang II infusion did not affect systolic blood pressure, card iac hypertrophy or weight of thoracic aorta. However, the high-dose Ang II infusion increased proteinuria by 58%, enhanced the urinary N-acetyl-beta-D-glucosaminase index by 77% and reduced the glomerular filtration rate by 37%. The impaired renal function was associated with a progression of glomerulosclerotic lesions. Neither tubular nor arterial lesions were exacerbated. The infusion did not influence prostacyclin production or urinary cyclic GMP excretion.
Conclusion: A subpressor dose of Ang II infusion impairs renal function with progression of glomerulosclerosis, and these alterations may be due to increased susceptibility of the glomerulus in Dahl-S rats to Ang II-induced injuries. Such a mechanism might underlie a predisposition to hypertension-induced organ damage seen in Dahl-S rats with salt-induced hypertension.

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gamma-Aminobutyric acid (GABA) is known to be involved in the regulation of blood pressure by modulating the neurotransmitter release in the central and peripheral sympathetic nervous systems. This study investigated the antihypertensive effect of green tea rich in GABA (GABA-rich tea) in young and old DahI salt-sensitive (S) rats. GABA-rich tea was made by fermenting fresh green tea leaves under nitrogen gas. In experiment 1, 21 11-month-old rats, fed a 4% NaCl diet for 3 weeks, were given water (group W), an ordinary tea solution (group T), or a GABA-rich tea solution (group G) for 4 weeks. The average GABA intake was 4.0 mg/rat per day. After 4 weeks of the treatment, blood pressure was significantly decreased in group G (176 +/- 4; P &lt; .01) compared with group W (207 +/- 9) or group T (193 +/- 5 mm Hg). Plasma GABA levels were more elevated in group G (111 +/- 54) than in group W (not detectable) or group T (14 +/- 8 ng/ mL; P &lt; .01 v G). In experiment 2, 21 5-week-old rats, fed a 4% NaCl diet, were divided into groups W, T, and G. The average GABA intake was 1.8 mg/rat per day. Body weight or chow and beverage consumption did not differ significantly among the three groups. After 4 weeks of the treatment, although blood pressure was comparable in groups W and T (165 +/- 3 v 164 +/- 5 mm Hg, mean +/- SE), it was significantly lower in group G (142 +/- 3 mm Hg) than in the other groups (P &lt; .01). Plasma aldosterone concentration was increased in group G compared to the other groups. Thus, GABA-rich tea seems not only to decrease the established high blood pressure but to prevent the development of hypertension in Dahl S rats fed a high salt diet.

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Interest in cardiovascular protection by calcium channel antagonists has grown over the past decade. We investigated the prevention of cardiac remodeling and renal injury by the long-acting calcium channel antagonist benidipine using 12 week-old Dahl salt-sensitive (Dahl S) rats fed a high-salt (4% NaCl) diet. Six-week benidipine treatment (10 mg/kg chow) decreased systolic blood pressure by 22% in Dahl S rats. This blood pressure reduction was associated with decreases in cardiac mass and weight of the aortic wall. Collagen content in the left ventricle tended to decline with benidipine treatment. In addition, glomerular filtration rate increased by 33% and arterial and glomerular lesions improved morphologically with this treatment. Regression of cardiac mass and collagen content in the left ventricle was due mainly to blood pressure reduction
however, collagen content in the low-pressure right ventricle was not only related to systemic blood pressure but to the severity of renal lesions. These data suggest that the calcium channel antagonist benidipine attenuates cardiac and renal injury in hypertensive Dahl S rats, and that part of the cardiac hypertrophy is due to a non-hemodynamic mechanism that might be responsible for, or be a consequence of, the lesions in the kidney. (Hypertens Res 1995
18: 245-253). © 1995, The Japanese Society of Hypertension. All rights reserved.

DOI： 10.1291/hypres.18.245

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER HEART ASSOC  

We investigated whether long-term infusion of kallikrein would attenuate renal injury in salt-induced hyper tension in Dahl salt-sensitive rats. A subdepressor dose of purified rat urinary kallikrein (700 ng/d IV) was infused by osmotic minipump for 4 weeks in male Dahl salt-sensitive rats fed a high salt (2% NaCl) diet. This dose did not affect the time-dependent elevation of blood pressure; however, urinary protein excretion was significantly decreased, and glomerular filtration rate was increased. These beneficial effects were reflected morphologically by an attenuation of the glomerulosclerotic lesions and tubular injury seen in the hypertensive Dahl salt-sensitive rats. Kallikrein infusion increased urinary excretion of bradykinin and stimulated excretion of cyclic GMP, suggesting that the kallikrein-kinin-prostaglandin and nitric oxide axes were enhanced by rat urinary kallikrein infusion. The alterations induced by kallikrein infusion were potentiated by the concomitant administration of the angiotensin-converting enzyme inhibitor alacepril. These studies indicated that long-term replacement with rat tissue kallikrein attenuates renal injury in hypertensive Dahl salt-sensitive rats.

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The antihypertensive effects of a novel adenosine A(2) receptor agonist, 2-octynyl adenosine (YT-146), were evaluated in Dahl salt-sensitive rats. After rats were fed a high-salt (8% NaCl) diet for 2 or 3 weeks, they received oral YT-146 (0.1 or 1.0 mg/kg) or vehicle as a single dose (acute study) or once daily for 10 days (chronic study). In the acute study, tail-cuff blood pressure (BP) and pulse rate (PR) were measured before and 3, 6, and 24 h after administration, and blood samples were collected 3 h after administration. In the chronic study, BP and PR were measured 3 and 24 h after administration and urine was collected for 24 h on day 9. blood samples were also collected 3 h after administration on day 10. BP was significantly lowered by 1.0 mg/kg of YT-146 in either the acute study (from 184 +/- 3 to 152 +/- 5 mm Hg, P &lt; .01) or the chronic study (from 226 +/- 4 to 201 +/- 2 mm Hg, P &lt; .01), while an increase in PR was not observed (acute study: from 382 +/- 8 to 366 +/- 3 beats/min; chronic study: from 420 +/- 8 to 411 +/- 8 beats/min). YT-146 had no effect on plasma renin activity (PRA), plasma aldosterone, vasopressin (ADH), and atrial natriuretic peptide (ANP) in the acute study. In the chronic study, neither PRA, plasma ADH concentration, urinary volume, urinary excretion of Na and K, nor creatinine clearance were affected, although plasma ANP concentration was significantly lowered (176 +/- 35 v 73 +/- 20 pmol/ mL, P &lt; .05) by 1.0 mg/kg of YT-146, compared with vehicle-treated rats. These data indicate that orally administered YT-146 shows antihypertensive effects without reflex tachycardia and has no remarkable effect on renal function in an animal model of hypertension.

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Objective: To investigate whether and how renin-angiotensin inhibition attenuates renal injury seen in salt-induced hypertension in Dahl salt-sensitive (Dahl-S) rats.
Methods: Dahl-S rats fed a high-salt (4% sodium chloride) diet for 6 weeks were treated with the angiotensin converting enzyme (ACE) inhibitor alacepril or the angiotensin receptor antagonist losartan for 4 weeks. Functional and morphological alterations in the kidney were investigated.
Results: Alacepril decreased systolic blood pressure (SBP). This SBP reduction was associated with the attenuation of cardiac and aortic wall hypertrophy and that of proteinuria and urinary N-acetyl-beta-D-glucosaminidase excretion. Kidney injuries, e.g. glomerular, arterial and tubular damage, were improved with alacepril treatment. Losartan decreased SBP to the same extent as alacepril, but neither renal function nor morphological structure was improved as was the case with alacepril. The response of the renal eicosanoid system to alacepril was inadequate, but cyclic GMP excretion, an indicator of nitric oxide formation, was significantly enhanced and lipid peroxidation in the kidney was decreased.
Conclusions: The beneficial effects of ACE inhibition on the renal injury in Dahl-S rats outrange those induced by the receptor antagonism. This might be due to multiple factors including an increased vasodepressor eicosanoid system, enhanced nitric oxide formation and possible inhibition of oxygen radical generation in the injured renal tissues.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN HEART JOURNAL, SECOND DEPT OF INTERNAL MED  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

Interest in the cardiovascular protective effects of calcium channel antagonists has increased in the past decade. We investigated prevention of vascular wall remodeling by the long-acting calcium channel antagonist pranidipine in 12-week-old Dahl salt-sensitive (SS) rats with high-salt-induced (4% NaCl) hypertension. Six-week pranidipine treatment (60 mg/kg chow) decreased systolic blood pressure (SBP) by 22% in SS rats. This BP reduction was associated with decreases in cardiac mass and weight of the aortic wall. Glomerular filtration rate (GFR) was increased by 33%, but this did not lead to a decrease in urinary protein or NAG excretion. Morphologic investigation demonstrated striking resolution of arterial injury (medial necrosis and/or hyperplasia, inflammatory cell infiltration, and thrombus formation) by 87% after pranidipine treatment. Glomerular sclerosis was also attenuated by 61%, whereas tubular injury was improved by only 28%. These morphologic changes were reflected in the findings that the capacity of kidney homogenate for generating lipid peroxides was significantly decreased and that collagen levels and pattern type became similar to those of normotensive salt-resistant (SR) rats. Pranidipine also attenuated hypertensive vasculopathy in small arteries of the middle cerebral arteries. Thus, the calcium channel antagonist pranidipine can attenuate the vascular injury that occurs in salt-induced hypertension, a promising property that implicates its clinical usage, particularly in essential hypertension with cardiovascular complications.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

We investigated the role of the vasoconstrictors endothelin-1 (ET-1) and thromboxane in renal protection by the beta(1)-selective adrenoceptor antagonist, bisoprolol, in Dahl salt-sensitive rats (Dahl S) and salt-resistant rats (Dahl R). Six-week bisoprolol treatment (20 mg/kg chow) reduced systolic blood pressure (SBP) by 14% in Dahl S rats fed a high-salt (4% NaCl) diet. This BP reduction was accompanied by a decrease in aortic wall thickness. ET-1 and thromboxane released from renal cortex was significantly decreased by 17 and 30% with bisoprolol, respectively. Other prostaglandin synthesis was unaffected. Renal function such as proteinuria, N-acetyl-beta-D-glucosaminidase (NAG) excretion, and glomerular filtration rate (GFR) was not influenced by bisoprolol. Morphologic investigation showed that bisoprolol significantly improved glomerular sclerosis by 29% and attenuated arterial damage by 71%, although tubular injury was not affected. The more severe the glomerulosclerotic lesions, the greater the generation of thromboxane and ET. The arterial lesions were positively correlated to thromboxane generation. These data indicate that long-term bisoprolol treatment reduces vasoconstrictive ET-1 and thromboxane generation and that these alterations may be partly responsible for the amelioration of glomerular and arterial injury in Dahl S rats.

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Objective: A pathogenetic role of altered alpha(2)-adrenoceptors in essential hypertension has been suggested, based on studies in humans and animals. To examine the role of the alpha(2)-adrenoceptor in genetically hypertensive rats, we compared the alpha(2)-adrenoceptor genes of stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats by restriction fragment length polymorphism analysis using human alpha(2)-adrenoceptor probes (alpha(2)-C10) and Dde I restriction endonuclease, and conducted a genetic cosegregation study.
Method: Five female WKY rats were bred with five male SHRSP. Eight pairs of F-1 Fats were mated in brother-sister pairs to yield an F-2 population of 84 rats. Systolic blood pressure was determined by tail-cuff sphygmomanometry. Direct arterial blood pressure was taken under ether anaesthesia just before the rats were killed. Southern blots were performed using alpha(2)C10 as a probe and the DNA from the F-2 generation.
Results: A restriction fragment length polymorphism of the SHRSP allele of a 1.6-kb fragment and a WKY rat allele oi a 0.9-kb fragment with a common band of 1.3 kb in SHRSP and WKY rats was found, as reported previously. The distribution of the genotype based on restriction fragment length polymorphism conformed to a 1:2:1 ratio in F-2 rats, as expected for a Mendelian trait. There was no significant difference in the blood pressure of F-2 rats with respect to alpha(2)-adrenoceptor genotype.
Conclusion: This study demonstrated that the alpha(2)-adrenoceptor gene restriction fragment length polymorphism distribution is a Mendelian trait in the F-2 rats of crossed SHRSP and WKY rats, but failed to show genetic cosegregation of this restriction fragment length polymorphism with blood pressure in this generation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER HEART ASSOC  

Recently, restriction fragment length polymorphism (RFLP) of ct,adrenergic receptor gene (alpha(2)-C10) digested with Bsu36I restriction enzyme has been reported in US populations. Therefore, we examined the association of this RFLP with essential hypertension by comparing the frequency of specific alleles for this gene in Japanese populations. The distribution of this RFLP was compared with that in US populations. Subjects were hypertensive patients with a family history of essential hypertension (n=56) and normotensive subjects whose parents had no history of essential hypertension (n=46). DNA was prepared from leukocytes. RFLP was determined by use of Southern blot analysis with an alpha(2)-C10 probe and Bsu36I. The frequencies of the major (12-kb) and minor (5.8-kb) alleles were 0.30 and 0.70 in hypertensive patients and 0.38 and 0.62 in normotensive subjects, respectively. The difference between observed alleles in all subjects in each group was not significant (chi(2)=1.33, P&gt;.1). The difference between the overall allelic frequency in Japan and that reported in US populations was significant. This study found no evidence for an association between alpha(2)-adrenergic receptor gene/BsuS6I RFLP and essential hypertension in Japan. However, the findings showed that the allele frequency in Japan differed from that reported in US populations.

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Language：Japanese   Publisher：The Japanese Society for Artificial Organs  

In this study, we measured the platelet concentration of calcium ions (Ca2+) and thrombin-stimulated platelet Ca2+ increases during hemodialysis in 33 patients (19 male, 14 female, mean age 55.2±2.3 years) with chronic ronal failire. The following results were obtained:1)Just after hemodialysis with a semi-synthetic membrane dialyzer, platelet Ca2+ increased significantly. However, this did not occur during hemodialysis with a synthetic menbrane dializer or during extra-corporeal ultrafiltration with both menbrane dialyzers. 2)The increase in platelet Ca2+ by thrombin stimulation at a dose ...

DOI： 10.11392/jsao1972.23.429

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：RAPID SCIENCE PUBLISHERS  

Objective: To investigate the effect of the angiotensin converting enzyme (ACE) inhibitor trandolaprilat on vascular smooth muscle cell growth, and to analyse its mechanism of action.
Design: Aortic vascular smooth muscle cells (VSMC) from Wistar-Kyoto rats were cultured, and cell proliferation was analysed using a cell synchrony technique.
Methods: Proliferative activity was assessed by [H-3]-thymidine uptake and doubling time. Protein synthesis was assessed by [H-3]-leucine incorporation. Actin formation was measured using sodium dodecylsulphate-polyacrylamide slab gel electrophoresis and a densitometric assay. The effect of trandolaprilat on translational protein synthesis was also examined using the cell-free protein synthesis system of reticulocyte lysate and messenger RNA from VSMC.
Results- Trandolaprilat decreased [H-3]-thymidine uptake and increased the doubling time of randomly cycling VSMC. The cell synchrony study revealed that this antiproliferative effect was due to increased transition time from S to G2-M. Decreased cell cycle progression during G2-M was reflected by inhibition of cellular protein synthesis during this period. Cellular protein in randomly cycling VSMC was also decreased by trandolaprilat. This decreased protein synthesis was probably produced by inhibition of RNA translation.
Conclusions. The ACE inhibitor trandolaprilat reduces VSMC proliferation by lengthening the G2-M phase of the cell cycle, and produces a decrease in cellular protein content. This effect is probably mediated by inhibition of protein synthesis at the translational level.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BUTTERWORTH-HEINEMANN  

We investigated the role of phospholipase A2 (PLA2) in cell cycle-dependent alterations of endogenous prostacyclin (PGI2) synthesis in aortic smooth muscle cells in culture (VSMC) from Wistar Kyoto rats. Randomly cycling VSMC generated more PGI2 than the stationary cells. Cell cycle analysis showed that PGI2 production capacity was increased from the G0/G1 through the early DNA synthetic (S) phases. Enzyme analysis revealed that, although there were different mechanisms underlying this increase in the PGI2 production during the GO/G1, the peak at 4 hours coincided with a sharp increase in PLA2 activity. This increase in PLA2 activity was preceded by an increased expression of functional PLA2 messenger RNA, and protein synthesis inhibition prevented most of the increase in PGI2 production at 4 hours. These data indicate that endogenous PGI2 generation is mainly increased during the G0/G1 period and that this event is secondary to de novo synthesis of PLA2 and probably, at least in part, to cyclooxygenase induction. This mechanism provides a negative feedback regulating VSMC proliferation.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE  

1. The localization of alpha-adrenoceptors in the plasma membranes of human kidney were investigated by radioligand binding, using an alpha1-antagonist, [H-3]-bunazosin, and an alpha2-antagonist, [H-3]-rauwolscine.
2. Both the maximum binding (B(max)) and dissociation constant (K(d)) of [H-3]-bunazosin were greater in the cortex than in the medulla. The B(max) of [H-3]-rauwolscine in the medulla was greater than in the cortex.
3. Thus, alpha1-adrenoceptors appeared to be localized predominantly in the cortex, while the alpha2-adrenoceptors were mainly present in the medulla of the human kidney.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Much interest in cicletanine, a novel antihypertensive drug, has grown because it uniquely stimulates prostacyclin (PGI2) production and may, thereby, provide further cardiovascular protection. We postulated that cicletanine may be an antioxidant, and assessed its ability to protect the kidney in Dahl salt-sensitive (Dahl S) rats on a high salt diet. Cicletanine eradicated in vitro a stable radical, DPPH, and decreased the lipid peroxidation both in rat brain homogenate and in a xanthine-xanthine oxidase (X-XOD) superoxide generating system. Furthermore, cicletanine attenuated the inhibition of PGI2 synthase activity by 15HPETE. However, cicletanine did not exhibit superoxide dismutase-like activity in X-XOD system, suggesting that it behaves primarily as a hydroxy radical scavenger. A 6 week cicletanine treatment reduced blood pressure in Dahl S rats fed a high salt diet, and ameliorated functional and morphological injury to the kidney. This attenuation of glomerular sclerosis correlated with the attenuation of lipid peroxidation in the kidney homogenate. These data indicate that cicletanine is an antioxidant that protects the kidney from salt-induced hypertension in Dahl salt-sensitive strain rats.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE INC  

Although adenosine is known to affect renal function through stimulating adenosine receptors, little is known about A1 receptors in human glomeruli. Thus, we attempted to identify the adenosine A1 receptor-cyclic AMP (cAMP) system in human glomeruli. Normal renal cortical tissues were obtained at nephrectomy of patients with renal cell carcinoma. Glomeruli were isolated using a graded sieving method or dissected manually under a stereomicroscope. Radioligand binding assay using 2-chloro-N-[H-3] cyclopentyl adenosine ([H-3]CCPA, an A1 agonist ligand) was performed at 30-degrees-C for 90 minutes. Cyclic AMP (cAMP) produced in glomeruli was measured after incubation with different concentrations of N6-cyclohexyladenosine (CHA; A1 agonist) and a phosphodiesterase inhibitor. The specific binding was saturated within 60 minutes and reversible by adding 1 mm of theophylline. Scatchard plot analysis revealed a single class of binding site (K(d) = 1.78 +/- 0.21 nm, B(max) = 271.7 +/- 35.8 fmol/mg protein). The specific binding was inhibited dose-dependently by various agents in an order suggesting A, receptor specificity. CHA inhibited the production of cAMP in microdissected human glomeruli. This inhibitory effect was antagonized by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; A1 antagonist). This is the first study revealing the presence of the A1 receptor-cAMP system in human glomeruli using a radioligand binding assay method and by measuring the cAMP production.

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In this study, the subcellular mechanism of impaired prostacyclin (PGI2) synthesis in the vascular system of Dahl salt-sensitive (Dahl S) rats was investigated. Arachidonate liberation in response to PDGF or bradykinin was decreased in cultured aortic smooth muscle cell (VSMC) from Dahl S rats, compared with Dahl salt-resistant (Dahl R) rats. Phospholipase C (PIP2-PLC) activity was lowered and the inositol 1,4,5-triphosphate content was also decreased in the VSMC from Dahl S rats. In fact, cytosolic calcium levels in basal and angiotensin-II stimulated conditions were significantly decreased in VSMC from Dahl S rats, compared with those in Dahl rats. There was no difference, however, in phospholipase A2 (PLA2) activity in the two strains. Moreover, the PLA2 enzyme properties, e.g., its Ca2+ requirement, pH profile, Km value and Vmax, were equal in Dahl S and Dahl R rats. The level of functional PLA2 messenger RNA was found to be greater in the VSMC from Dahl S rats. Similarly, PGI2 synthesis was reduced in Dahl S rats and this was associated with an unaltered PLA2 concentration and decreased PIP2-PLC activity in the arterial wall. Thus, these data indicate that dysfunction of receptor-mediated PLA2 activation is responsible for altered PGI2 synthesis in Dahl S rats. This finding is likely mediated by a decrease in phosphoinositides metabolism. © 1993, The Japanese Society of Hypertension. All rights reserved.

DOI： 10.1291/hypres.16.105

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Language：Japanese   Publisher：The Japanese Society of Internal Medicine  

DOI： 10.2169/naika.82.1713

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

We investigated the regulatory effects of the vasoconstrictor thromboxane A2 on the proliferation of vascular smooth muscle cells (VSMC) from Wistar-Kyoto rats using 9,11-epithio-11,12-methano-thromboxane A2 (STA2), a stable analogue of thromboxane A2. STA2 dose dependently increased incorporation of [H-3]thymidine into DNA in randomly cycling VSMC and significantly shortened the doubling time. Cell cycle analysis revealed that the increased cell cycle progression was primarily due to a rapid transition from the DNA synthetic (S) to the G2/mitotic (M) phase. Moreover, STA2 enhanced protein synthesis in VSMC during the G2/M phase, whereas the protein synthesis was unaffected in the G0/G1 period. In fact, STA2 prompted the cells in G2/M phase to synthesize actin, a major cytoskeleton protein. Conversely, inhibition of protein synthesis by puromycin retarded the transition from S to G2/M. In addition, depolymerization of the actin molecules by cytochalasin D offset the quick progression to the G2/M phase by STA2. These data indicate that thromboxane A2 stimulates the cell cycle progression in VSMC primarily through a rapid transition from S to G2/M. This enhanced progression is attributable partly to a rapid buildup of the cytoskeleton proteins during the G2/M period.

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Objective: To study the effects of genetics on the response of platelet alpha2-adrenoceptors to a change in salt intake.
Methods: Biochemical measurements and radioligand binding assays in platelets were performed in 11 normotensive male university students with a family history of essential hypertension (FH+) and in 17 students without a family history of hypertension (FH-). The 28 students were fed a high-sodium diet for 7 days and a low-sodium diet for 7 days.
Results: In FH+ subjects the number of alpha2-adrenergic receptors on platelet membrane fractions increased significantly from the high-sodium diet to the low-sodium diet, even though plasma noradrenaline concentrations tended to increase with the low-sodium diet. There was no change in the number of alpha2-adrenoceptors in the FH-group. In both groups the radioligand binding affinity was decreased during a low-sodium period compared with in a high-sodium period.
Conclusion: In the FH+ subjects the change in platelet alpha2-adrenoceptors associated with altered sodium status was similar to that seen in patients with salt-sensitive hypertension, suggesting that there is a genetic susceptibility to sodium.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Renal alpha-2-adrenoceptors are known to be increased in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). To investigate whether this difference affects the second messenger system, we examined the effect of alpha-2-adrenoceptor stimulation on the formation of cAMP in microdissected glomeruli and proximal convoluted tubules obtained from the kidneys of SHR and WKY. The formation of glomerular cAMP, which was stimulated by parathyroid hormone (PTH), was inhibited by alpha-2-adrenoceptor stimulation. In contrast, the inhibitory effect of alpha-2-adrenoceptor stimulation on PTH-induced cAMP formation in proximal convoluted tubules was not significantly different between SHR and WKY. These results confirm the inhibitory action of alpha-2-adrenoceptors on the formation of cAMP in glomeruli and proximal tubules and suggest that the greater inhibitory effect on glomerular cAMP formation in SHR may reflect an increase in alpha-2-adrenoceptor density in SHR kidneys.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

mRNA levels for renin in the adrenal gland and kidney were measured by ribonuclease protection assay (RPA). Renin mRNA was not detected by RPA in aldosteronoma and kidney tissues obtained from two patients with primary aldosteronism (PA). In these patients, the PRA values, plasma concentrations of active renin (ARC), and total renin (TRC = ARC + prorenin) were below the assay limit (&lt; 0.03 ng/L.s, 2.5 ng/L, and 10 ng/L, respectively). On the other hand, renin mRNA was recognized by RPA in aldosteronoma and kidney tissues obtained from two other patients with PA treated with 50 mg/day spironolactone for more than 2 months. Their TRC values were 49.8 and 16.6 ng/L, but their PRA and ARC were undetectable. Renin mRNA content was greater in normal adrenocortical tissue and in the normal kidneys obtained from three hypertensive patients with renal cell carcinoma. In these patients, the mean values of PRA, ARC, and TRC were 0.28 +/- 0.03 (mean +/- SD) ng/L.s, 18.4 +/- 7.8 ng/L, and 110 +/- 15 ng/L, respectively.
This is the first report of the lack of renin gene expression in aldosteronoma and kidney tissues obtained from untreated patients with PA. Furthermore, treatment with spironolactone resulted in an increase in the levels of renin mRNA in the aldosteronoma and kidney tissues of patients with PA.

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：INSERM / JOHN LIBBEY EUROTEXT  

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Language：Japanese   Publisher：The Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/jscpt.23.137

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Other Link： http://search.jamas.or.jp/link/ui/1993002732

Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：INSERM / JOHN LIBBEY EUROTEXT  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PORTLAND PRESS  

1. To assess the role of the vasodepressor prostaglandin system in the antihypertensive properties of beta-adrenoceptor antagonist, we investigated the alterations of prostaglandin generation in the kidney and in the aorta when spontaneously hypertensive rats were treated with atenolol for 2 weeks.
2. The blood pressure reduction was associated with an increase in urinary sodium excretion and urinary prostaglandin E2 excretion. The sodium excretion was positively related to the prostaglandin E2 excretion.
3. Basal release of prostaglandin E2 from the sliced renal cortex was enhanced by the atenolol treatment. Prostacyclin-generating capacity in the aortic wall was also significantly increased.
4. Atenolol treatment stimulated prostaglandin synthesis in the kidney and vascular wall in a dose-dependent manner. However, atenolol per se did not directly stimulate prostaglandin synthesis in the vascular wall.
5. Inhibition of prostaglandin generation by a cyclooxygenase inhibitor, indomethacin, was associated with attenuation of the antihypertensive effects of atenolol.
6. Thus these data indicate that sub-chronic atenolol treatment stimulates vasodepressor prostaglandin generation in the kidney and in the aortic vessels, and this shares the antihypertensive effects of this drug with the mechanism of beta-adrenergic antagonism probably mediated through vasorelaxation and natriuresis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Prostacyclin (PGI2) synthase is one of the key enzymes for vasodepressor PGI2 biosynthesis in the vascular wall. In this study, we attempted to define the alterations in PGI2 synthase and its role in the PGI2 generation in the vascular wall of deoxycorticosterone acetate (DOCA)-salt rats. The PGI2-generating capacity was enhanced significantly when DOCA-salt rats established hypertension, whereas the generation of other arachidonate metabolites, eg, PGE2, PGF2-alpha, and thromboxane, was unaltered. Moreover, the increase in PGI2 generation was associated with an increase in PGI2 synthase activity in the vascular wall. Indeed, the averaged PGI2 generating capacity was closely correlated to the averaged PGI2 synthase activity in DOCA-salt hypertensive rats and three lines of control rats. Incontrast, phospholipase C and phospholipase A2, both of which liberate arachidonate for PGI2 synthesis, were rather lowered in DOCA-salt hypertensive rats. These data clearly indicate that vascular PGI2 generation is increased in the development of DOCA-salt hypertension and that PGI2 synthase is mainly responsible for this enhancement. The increased PGI2 synthase may be relevant to the blood pressure elevation and is expected to have beneficial effects on the vascular protection in hypertension.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CHURCHILL LIVINGSTONE  

We attempted to investigate the alterations in the vasoconstrictor thromboxane (TXA2) system in the kidney when spontaneously hypertensive rats (SHR) were treated subchronically with atenolol, a beta 1-adrenoceptor antagonist. Atenolol treatment (30 mg/kg body weight per day for 2 weeks) reduced systolic blood pressure by 11%, being accompanied by a decrease in heart rate. This treatment strikingly decreased thromboxane content in the renal cortex by 48% (p &lt; 0.05), whereas the tissue content was unaltered for prostaglandin E2 (PGE2) or slightly decreased for prostacyclin (PGI2). These alterations in the eicosanoid system led to an increase in the ratio of PGE2/TXA2 and of PGI2/TXA2. Similarly, thromboxane content in the renal papilla was lowered significantly with atenolol treatment, which raised the ratio of PGE2 to TXA2. Thromboxane reduction was not observed in the aortic walls and heart. However, in the vascular walls, PGI2 synthesis was markedly stimulated with atenolol treatment, resulting in an increase in the ratio of PGI2 to TXA2. Thus, these data indicate that subchronic atenolol-treatment inhibits the thromboxane system in the kidney, thereby shifting the eicosanoid system towards a vasodilator state. These alterations contribute, in part, to the anti-hypertensive properties of atenolol in genetic hypertension.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN CIRCULATION SOC  

We investigated the alterations of phospholipase C activity in the kidney and arterial wall of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Neither DOCA nor salt administration alone affected phospholipase C activity in the kidney and arterial wall. In contrast, when the rats were given both DOCA and salt and developed high blood pressure, the phospholipase C activity became greater in the outer and inner medulla (papilla) while the enzyme activity was reduced significantly in the renal cortex and arterial wall. Such an increase in phospholipase C activity was not observed in the kidney of a genetic rat for spontaneous hypertension. Moreover, the phospholipase A2 activity was also stimulated in the renal medulla of DOCA-salt hypertensive rats. Thus, these data indicate that DOCA-salt hypertension is associated with an increase in phospholipase C activity in the renal medulla, which seems primary to the development of DOCA-salt hypertension.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer-Verlag  

A case is presented in which suprarenal neurilemoma was associated with paroxysmal attacks of hypertension, headache and sweating with elevated plasma and urinary catecholamines. Pheochromocytoma was excluded using an overnight clonidine suppression test. Ultrasonography, computed tomography and magnetic resonance imaging, which showed cystic mass with a pedicle continuing to the widened intervertebral foramen, were helpful for the preoperative diagnosis of retroperitoneal neurilemoma. The excised tumor was revealed to be benign neurilemoma and contain detectable levels of adrenaline, noradrenaline and dopamine. The relationships between tumor catecholamines and clinical manifestations will be discussed. © 1991 Springer-Verlag.

DOI： 10.1007/BF01646948

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

A single high affinity binding site for an alpha-2-adrenoceptor in human coronary arteries was identified by radioligand binding assay. Human coronary arteries were obtained at autopsy within 6 hours of death. A crude membrane solution was incubated with (H-3)-rauwolscine at 25-degrees-C for 30 min. The binding of (H-3)-rauwolscine was rapidly saturable and reversible. Kd was 1.2 +/- 0.2 (SE) nM and Bmax 22 +/- 3 fmol/mg protein. This is the first study which has shown the presence of an alpha-2-adrenoceptor in human coronary arteries using a radioligand binding assay method.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

We defined the role of a serotonin type 2 receptor antagonist, ketanserin, in the growth of aortic vascular smooth muscle cells (VSMCs) from Wistar rats, using cell culture and cell synchrony methods. Deoxyribonucleic acid (DNA) replication in the G0/G1- or G1/S-synchronized VSMCs was assessed by [H-3]thymidine uptake into DNA. Ketanserin at 2 x 10(-5) M significantly decreased the thymidine uptake by 48% in the proliferating VSMCs, whereas methysergide, a nonspecific serotonin inhibitor, unaffected the thymidine uptake. Ketanserin at 10(-5) M did not influence the duration of the G1 resting period. However, this dose of ketanserin significantly lowered DNA replication in the DNA synthetic (S) period in a dose-dependent manner. Neither methysergide nor the alpha-1-adrenoceptor antagonist, prazosin, affected DNA synthesis in the S period. Ketanserin exhibits antiproliferative effects on rat VSMC growth probably through the suppression of DNA replication in the S phase. This property would also contribute to the vascular protective effects of ketanserin with its well-documented antihypertensive action.

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Language：Japanese   Publishing type：Research paper (international conference proceedings)  

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A direct radioimmunoassay (RIA) for plasma active renin concentration (ARC) was evaluated by using plasma samples obtained from hospitalized normal volunteers and hypertensive patients. The direct renin RIA was performed by using a pair of anti-renin monoclonal antibodies and a sandwich method. It is suggested that an agitator should be used during the incubation, because the magnetic solid phase was precipitated and could not be suspended well in plasmas. Further, the thawed reagents should not be used for the assay. A highly significant correlation (r = 0.96, p &lt
0.01) was found between ARC and enzymatic activity of renin (PRA) in plasma samples obtained from hypertensive patients. The mean values of ARC were 22.8 ± 3.6 pg/ml in normal subjects, 22.5 ± 5.3 in patients with EH having medium levels of PRA, 113.7 ± 11.7 in patients with renovascular hypertension, and undetectable in patients with primary aldosteronism. The results indicated good and reliable performance of the direct renin RIA, which is clinically useful to investigate the renin-angiotensin system.

DOI： 10.1097/00000441-199009000-00002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：RAPID SCIENCE PUBLISHERS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT-RAVEN PUBL  

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Language：English   Publishing type：Research paper (scientific journal)  

The effects of synthetic human atrial natriuretic peptide (ANP) on the release of catecholamines, aldosterone, or cortisol were observed in human adrenal tumors obtained surgically from patients with pheochromocytoma, primary aldosteronism, or Cushing's syndrome, respectively. Each tumor tissue or adjacent normal cortical tissue was sectioned into slices, which were incubated in medium-199 in the presence or absence of adrenocorticotrophin (ACTH) and ANP. The amounts of epinephrine, norepinephrine, aldosterone, or cortisol released into the medium were measured. Existence of ANP receptors on the adrenal tissues was examined by binding assays, affinity labeling, and immunohistochemistry. Release of catecholamines from pheochromocytoma tissues was inhibited by ANP, and the presence of the ANP receptor of phenochromocytoma was further demonstrated by both binding assays and affinity labeling
Scatchard analysis revealed a single class of binding sites for ANP with a K(d) of 1.0 nM and a B(max) of 0.4 pmol/mg of protein and the molecular size was estimated as 140 and a 70 kDa under nonreducing and reducing conditions, respectively. The presence of ANP receptors in phenochromocytoma was demonstrated by immunohistochemistry. ANP inhibited both basal and ACTH-stimulated aldosterone secretion in the slices of normal cortex, and localization of ANP receptors in zona glomerulosa cells was also demonstrated. However, ANP did not inhibit basal and ACTH-stimulated aldosterone and cortisol secretion in both tissue slices from aldosteronoma and Cushing's adenoma. Consistent with these observations, the absence of ANP receptors in adenoma tissues was determined by binding assays, affinity labeling, and immunohistochemistry. In conclusion, we identified the functional ANP receptors in pheochromocytoma and normal zona glomerulosa cells, but not in aldosterone and Cushing's adenoma.

DOI： 10.1097/00005344-198905006-00004

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Language：English   Publishing type：Research paper (scientific journal)  

In order to assess the roles of vasoconstrictor thromboxane in the antihypertensive action of α1 adrenoceptor antagonist, we explored the influences of OKY-046, a selective thromboxane inhibitor, on the antihypertensive effects of bunazosin in spontaneously hypertensive rats (SHR). 2-week antihypertensive treatment with bunazosin (0.5 mg/kg/day) did not produce a significant decrease of systolic blood pressure in SHR, as compared to untreated controls. The blood pressure reduction was associated with a decreases of PGI2/TXA2 in vascular eicosanoids generation (p&lt
0.02) and an increase of TXA2 excretion in urine (p&lt
0.05). A combination treatment with OKY-046 almost completely abolished the enhanced TXA2 generation in the vascular wall and kidney, which was strikingly associated with a potentiation of the blood pressure reduction by bunazosin treatment (176 vs 186 mmHg, p&lt
0.01). Bunazosin directly stimulated TXA2 biosynthesis in vascular smooth muscle cells in culture in a dose-dependent manner. Thus, these data clearly indicate that bunazosin, a quinazoline derivative, enhances vasoconstrictor TXA2 system in the vascular wall and kidney possibly through direct actions, which would attenuate the antihypertensive effects of α1 adrenoceptor antagonism by bunazosin treatment. © 1989, Japanese Society of Nephrology. All rights reserved.

DOI： 10.14842/jpnjnephrol1959.31.969

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Language：English   Publishing type：Research paper (scientific journal)  

We designed experiments to reveal the effects of a S2 serotonergic receptor antagonist, ketanserin, on the vascular eicosanoid system and the relevance to medial hyperplasia in spontaneously hypertensive rats (SHR). 2-week ketanserin treatment (5 mg/kg/day) significantly decreased systolic blood pressure by 7% when compared to untreated SHR. The blood pressure reduction was associated with a significant decrease in vascular thromboxane A2 (TXA2) generation and sustained prostacyclin (PGI2) production, thereby shifting PGI2/ TXA2 ratio toward vasodilatation. In contrast, the trichlormethiazide treatment, which achieved blood pressure reduction to almost the same extent, significantly decreased PGI2/TXA2 ratio. Vasodilator eicosanoids, e. g. PGI2, PGE2 and PGD2, dose-dependently decreased (3H)-thymidine uptake by vascular smooth muscle cells in culture whereas vasoconstrictor TXA2 enhanced (3H) thymidine uptake in a dose dependent manner. Indeed, 2×10−5 M ketanserin significantly decreased (3H)thymidine uptake by vascular smooth muscle cells by 48% although the same dose of methysergide, nonspecific serotonin inhibitor, did not affect the uptake by vascular smooth muscle cells. These results clearly indicate that the blood pressure reduction in ketanserin treatment is uniquely associated with a decrease in vascular thromboxane generation, and that it is possibly beneficial to protect vascular wall against medial hyperplasia of vascular smooth muscle cells, an integral component of arterial sclerotic changes in hypertension. © 1989, Japanese Society of Nephrology. All rights reserved.

DOI： 10.14842/jpnjnephrol1959.31.31

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARCEL DEKKER INC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa Healthcare  

The physiological role of numerically predominant α2 -adrenoceptor in the kidney is still unknown. This study examined the effect of α2zadrenoceptor stimulation on the production of cAMP from isolated human glomeruli. Unaffected portions of human kidneys which had been removed because of renal cell carcinoma were used for the study. Glomeruli were dissected manually under a stereo microscope. In these glomeruli, α2-adrenoceptor stimulation with epinephrine in the presence of propranolol inhibited significantly parathyroid hormone-dependent increases in cAMP production. This inhibitory effect of epinephrine was removed by adding a specific α2-adrenoceptor antagonist, yohimbine, indicating that the inhibitory effect of epinephrine on cAMP formation was due to α2-adrenoceptor stimulation. Thus, α2- -adrenoceptors are involved in the inhibition of cAMP production in human glomeruli. © 1989 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

DOI： 10.3109/10641968909045431

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：RAPID SCIENCE PUBLISHERS  

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Language：English   Publishing type：Research paper (scientific journal)  

The effect of synthetic alpha-human atrial natriuretic peptide (ANP) on aldosterone secretion was studied in human aldosterone producing adrenocortical adenoma obtained surgically from a patient with primary aldosteronism and in human apparently normal adjacent adrenal cortical tissues obtained from a patient with pheochromocytoma, in vitro. Apparently normal adrenal cortical tissue responded to ANP with the known inhibition of aldosterone secretion. In contrast, the aldosterone producing adenoma did not respond to ANP. When stimulated by either ACTH or angiotensin II, there is no inhibition by ANP in the adenoma tissue, whereas normal tissue was inhibited. Immunohistochemical examination utilizing an ANP-receptor antiserum demonstrated that there was no evidence of binding site in the cortical adenoma, in contrast, zona glomerulosa cells in the cortical tissues adjacent to either aldosterone producing adenoma or pheochromocytoma were densely stained. This apparent lack of ANP-receptors is an associated finding with the hypersecretion of aldosterone in the aldosterone prducing adenoma. © 1988 Academic Press, Inc.

DOI： 10.1016/S0006-291X(88)80676-4

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Language：English   Publishing type：Research paper (scientific journal)  

Vascular eicosanoids (prostaglandins and thromboxanes) system is involved in the development or regression of arteriosclerotic changes as well as the regulation of vascular wall contractility. Thiazide diuretics have been reported to exhibit an arteriosclerotic effect, which may cancel the beneficial effects due to the hypotensive action of the agents. To assess the role of vascular eicosanoids system in the effects of thiazide therapy, we examined alterations of the eicosanoids system in aortic walls of spontaneously hypertensive rats (SHR) which had been treated with trichlormethiazide (8 mg/kg/day) for 2 weeks. Thiazide treatment significantly decreased systolic blood pressure in SHR by 10%, which was associated with a significant reduction in vascular prostacyclin (PGI2) generation by 29%. Thiazide diuretic lowered the PGI2 production in both the aortic walls and cultured vascular smooth muscle cells (VSMCs) of SHR. A similar inhibitory effect was observed with furosemide. In contrast, the PGI2 generation was stimulated by a non-thiazide diuretic, indapamide. The thiazide diuretic significantly lowered PGI2 synthase activity in VSMCs of SHR without affecting the activities of phospholipase A2 and phos-pholipase C. Thus, these data indicate that vascular PGI2 generation is impaired in a prolonged treatment with trichlormethiazide partly through its direct inhibitory actions on PGI2 synthase. The lowered PGI2 generation is possibly related to the unbeneficial effects of thiazide diuretics on the sclerotic changes in the vascular wall. © 1988, Japanese Society of Nephrology. All rights reserved.

DOI： 10.14842/jpnjnephrol1959.30.1339

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To define the roles of vascular prostacycl in (PGI2) synthase for PGI2 generation in deoxycorticosterone acetate (DOCA)-salt hypertension, we investigated PGI2 synthase, phospholipase A2 and phospholipase C activities in the aortic wall of DOCAsalt prehypertensive and established hypertensive rats. Vascular PGI2 generation in the DOCA-salt hypertensive rats was increased by 91%, and was associated with an 88% increase in PGI2 synthase activity and lowered phospholipase C and A2 activity. In the prehypertensive stage, DOCA-salt rats showed reduced vascular PGI2 generation. Prostacyclin synthase activity was equal to that of controls. These data clearly suggest that DOCA-salt hypertensive rats increase their vascular PGI2 generation when they develop hypertension, and that this may be due to the activation of vascular PGI2 synthase. © Gower Academic Journals Ltd.

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Language：English   Publishing type：Research paper (scientific journal)  

Pheochromocytoma, a catecholamine-secreting adrenomedullary tumor, has been shown to contain the functional receptor for human atrial natriuretic peptide(h-ANP). Release of catecholamines from tissue slices of pheochromocytoma was inhibited by h-ANP in a dose-dependent manner. Binding assays using 125I-ANP revealed a single class of high affinity binding sites for ANP. When covalently tagged with 125I-ANP and electrophoresed under non-reducing and reducing conditions, the receptor migrated as a 140-kDa band and a 70-kDa band, respectively, reflecting its disulfide-linked subunit structure. The presence of ANP receptor in pheochromocytoma was further demonstrated by immuno-histochemistry
the tumor was positively stained with an anti-receptor antiserum. The antiserum was also useful to establish the zona glomerulosa localization of ANP receptor in the normal human adrenal gland. © 1987.

DOI： 10.1016/0006-291X(87)91108-9

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Publishing type：Book review, literature introduction, etc.  

© 2019 The Author(s). Since 2015, the Committee for International Communication on Academic Research of the Japanese Society for Dialysis Therapy has held its Asian symposium during the society's Annual Congress to discuss the present status of and demand for dialysis therapy in Asian countries in order to identify needs and find ways to contribute to these countries in the area of dialysis therapy. Five manuscripts are presented here by symposium participants from Cambodia, Laos, Bhutan, Mongolia, and Indonesia from the Asian symposium of 2016. With progress in economic development, hemodialysis (HD) therapy has now been introduced in all countries worldwide. However, the cost of HD is extremely high compared with typical incomes in every country, and as of 2016, many countries still have not established national health insurance systems. In Cambodia and Laos, for example, patients must bear 100% of the cost for dialysis. In contrast, in Bhutan, the government bears all costs and the patients need not pay at all. In Mongolia and Indonesia, dialysis is almost completely covered by national health insurance. Dialyzers tend to be reused in Cambodia, Laos, and Indonesia. In Mongolia and Bhutan, dialyzers are single-use only. Continuous ambulatory peritoneal dialysis is available in Mongolia and Indonesia but is just starting to be introduced in Laos; it is not available in Cambodia and Bhutan. In Cambodia and Laos where there is no national health insurance system, patients with lower socioeconomic status come to the HD center only when they have enough money to pay for an HD session. Viable health insurance systems should be established as soon as possible. However, this will ultimately depend on the countries' economic development.

DOI： 10.1186/s41100-019-0206-y

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