記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hypertension is an uncommon manifestation of Behcet's disease, which is also an uncommon cause of renovascular hypertension. We herein report a case of malignant hypertension associated with unilateral renal artery stenosis due to vascular Behcet's disease. A 19-year-old man, who had no significant medical history, was referred to ophthalmology at our hospital because he was suspected to have uveitis and Vogt-Koyanagi-Harada syndrome. In addition to poor eyesight, he had been aware of a fever, loss of appetite, and weight loss for a month. He was admitted with markedly elevated blood pressure (222/140 mmHg), hypertensive retinopathy, and acute kidney injury, who was diagnosed with malignant hypertension. Laboratory findings showed high plasma renin activity and plasma aldosterone concentration, hypokalemia, and elevated inflammatory response. Computed tomography showed an atrophic right kidney and a compensatorily enlarged left kidney. Renal computed tomography angiography revealed severe and diffuse stenosis of the right renal artery, and stenosis of the ostium of celiac artery. Since he was suspected to have uveitis and his inflammatory responses were elevated on admission, we listed Behcet's disease as a differential diagnosis. Medical interview and examination focusing on Behcet's disease revealed that the patient had recurrent oral aphthous lesions and folliculitis, and a positive pathergy test, which led to the patient being diagnosed with vascular Behcet's disease. After admission, his blood pressure was well controlled with multiple antihypertensive drugs including an angiotensin receptor/neprilysin inhibitor, and his oral aphthous lesions and skin lesion were improved with colchicine. When young men who are at a higher risk for vascular Behcet's disease show renovascular hypertension with an elevated inflammatory reaction, vascular Behcet's disease should be considered as a differential diagnosis.

DOI： 10.1007/s13730-024-00918-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Peripheral artery disease (PAD) severely impairs patient prognosis and quality of life (QOL). Although lipoprotein apheresis (LA) has been applied to patients with PAD and elevated serum atherogenic lipoproteins, we hypothesized that LA can be effective for treating PAD even in patients with controlled serum lipoproteins through pleiotropic anti-atherosclerotic effects beyond lipoprotein removal. This study aimed to evaluate the efficacy of LA in patients with treatment-resistant PAD and controlled serum lipoproteins focusing on QOL. METHODS: In a single-arm prospective study, 30 patients with refractory PAD who had controlled serum lipoproteins underwent sequential LA sessions using dextran sulfate adsorption columns, aiming to complete 10 sessions. The ankle-brachial pressure index (ABI) and vascular QOL (VascuQOL) score were evaluated as the primary outcomes. Secondary outcomes included reactive hyperemia index (RHI) and biological antioxidant potential (BAP) as an endothelial function test and serum antioxidative-capacity evaluation, respectively. RESULTS: ABI significantly increased after LA sessions (pre-treatment 0.60±0.09 vs. post-treatment 0.65±0.13, p=0.023). Total VascuQOL score (3.7±1.1 vs 4.6±1.1, p＜0.001) and RHI (1.70±0.74 vs 2.34±1.76, p=0.023) significantly improved after the LA sessions. BAP tended to increase after the LA sessions, and the change reached statistical significance 3 months after treatment. CONCLUSION: ABI and QOL improved after a series of LA sessions in conventional treatment-resistant PAD patients with controlled serum lipoprotein levels. Increased antioxidative capacity and ameliorated endothelial function were observed after the LA treatment.

DOI： 10.5551/jat.64639

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The progress in the research field of diabetic kidney disease (DKD) has been disturbed by the lack of reliable animal models. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R and selectively inhibits pathological AT1R signaling. In this study, we investigated whether overactivation of the renin-angiotensin system (RAS) through a combination of ATRAP deletion with Ang II stimulation developed a progressive DKD model in C57BL/6 mice, which are resistant to the development of kidney injury. Eight-week-old male systemic ATRAP-knockout mice on the C57BL/6 strain (KO) and their littermate wild-type mice (Ctrl) were divided into five groups: 1) Ctrl, 2) Ctrl-streptozotocin (STZ), 3) KO-STZ, 4) Ctrl-STZ-Ang II, and 5) KO-STZ-Ang II. Ang II was administered for 6 weeks from 4 weeks after STZ administration. At 10 weeks after STZ administration, mice were euthanized to evaluate kidney injuries. Neither ATRAP deletion alone nor Ang II stimulation alone developed a progressive DKD model in STZ-induced diabetic C57BL/6 mice. However, a combination of ATRAP deletion with Ang II stimulation accelerated the development of DKD as manifested by overt albuminuria, glomerular hypertrophy, podocyte loss, mesangial expansion, kidney interstitial fibrosis and functional insufficiency, concomitant with increased angiotensinogen and AT1R expression in the kidneys. In STZ-induced diabetic C57BL/6 mice that are resistant to the development of kidney injury, the combination of ATRAP deletion and Ang II stimulation accelerates the development of DKD, which may be associated with intrarenal RAS overactivation.

DOI： 10.1038/s41440-023-01496-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection. METHODS AND RESULTS: C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI. CONCLUSION: PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria.

DOI： 10.1093/ehjopen/oead098

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The renin-angiotensin system in the brain plays a pivotal role in modulating sympathetic nerve activity and contributes to the pathogenesis of hypertension. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R while suppressing pathological overactivation of AT1R signaling. However, the pathophysiological function of ATRAP in the brain remains unknown. Therefore, this study aims to investigate whether ATRAP in the paraventricular nucleus (PVN) is involved in neurogenic hypertension pathogenesis in Ang II-infused rats. The ATRAP/AT1R ratio, which serves as an indicator of tissue AT1R hyperactivity, tended to decrease within the PVN in the Ang II group than in the vehicle group. This suggests an Ang II-induced hyperactivation of the AT1R signaling pathway in the PVN. Lentiviral vectors were generated to stimulate ATRAP expression. At 6 weeks of age, rats were microinjected with LV-Venus (Venus-expressing lentivirus) or LV-ATRAP (Venus-ATRAP-expressing lentivirus). The rats were then randomly divided into four groups: (1) Vehicle/LV-Venus, (2) Vehicle/LV-ATRAP, (3) Ang II/LV-Venus, and (4) Ang II/LV-ATRAP. Two weeks after microinjection, vehicle or Ang II was administered systemically for 2 weeks. In the Ang II/LV-ATRAP group, systolic blood pressure at 1 and 2 weeks following administration was significantly lower than that in the Ang II/LV-Venus group. Furthermore, urinary adrenaline levels tended to decrease in the Ang II/LV-ATRAP group than in the Ang II/LV-Venus group. These findings suggest that enhanced ATRAP expression in the PVN suppresses Ang II-induced hypertension, potentially by suppressing hyperactivation of the tissue AT1R signaling pathway and, subsequently, sympathetic nerve activity.

DOI： 10.1038/s41440-023-01480-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Dysregulation of angiotensin II type 1 receptor-associated protein (ATRAP) expression in cardiovascular, kidney, and adipose tissues is involved in the pathology of hypertension, cardiac hypertrophy, atherosclerosis, kidney injury, and metabolic disorders. Furthermore, ATRAP is highly expressed in bone marrow-derived immune cells; however, the functional role of immune cell ATRAP in obesity-related pathology remains unclear. Thus, we sought to identify the pathophysiological significance of immune cell ATRAP in the development of visceral obesity and obesity-related metabolic disorders using a mouse model of diet-induced obesity. METHODS: Initially, we examined the effect of high-fat diet (HFD)-induced obesity on the expression of immune cell ATRAP in wild-type mice. Subsequently, we conducted bone marrow transplantation to generate two types of chimeric mice: bone marrow wild-type chimeric (BM-WT) and bone marrow ATRAP knockout chimeric (BM-KO) mice. These chimeric mice were provided an HFD to induce visceral obesity, and then the effects of immune cell ATRAP deficiency on physiological parameters and adipose tissue in the chimeric mice were investigated. RESULTS: In wild-type mice, body weight increase by HFD was associated with increased expression of immune cell ATRAP. In the bone marrow transplantation experiments, BM-KO mice exhibited amelioration of HFD-induced weight gain and visceral fat expansion with small adipocytes compared BM-WT mice. In addition, BM-KO mice on the HFD showed significant improvements in white adipose tissue metabolism, inflammation, glucose tolerance, and insulin resistance, compared with BM-WT mice on the HFD. Detailed analysis of white adipose tissue revealed significant suppression of HFD-induced activation of transforming growth factor-beta signaling, a key contributor to visceral obesity, via amelioration of CD206+ macrophage accumulation in the adipose tissue of BM-KO mice. This finding suggests a relevant mechanism for the anti-obesity phenotype in BM-KO mice on the HFD. Finally, transcriptome analysis of monocytes indicated the possibility of genetic changes, such as the enhancement of interferon-γ response at the monocyte level, affecting macrophage differentiation in BM-KO mice. CONCLUSION: Collectively, our results indicate that ATRAP in bone marrow-derived immune cells plays a role in the pathogenesis of visceral obesity. The regulation of ATRAP expression in immune cells may be a key factor against visceral adipose obesity with metabolic disorders.

DOI： 10.1016/j.metabol.2023.155706

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To compare the therapeutic effects of glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 receptor agonists (GLP-1RAs) or GLP-1RAs in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP-1RAs or GIP/GLP-1RAs in Japanese patients with T2D were selected. A network meta-analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). RESULTS: A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] -0.52 [-0.96; -0.08] and - 1.23 [-1.64; -0.81]; BW: -5.07 [-8.28; -1.86] and -6.84 [-8.97; -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1RAs, such as dulaglutide, liraglutide and lixisenatide. CONCLUSIONS: Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP-1RA treatment strategies in Japanese patients with T2D.

DOI： 10.1111/dom.15312

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with primary aldosteronism (PA) have a higher risk of cardiovascular disease (CVD) than essential hypertension due to underlying hyperaldosteronism. However, the association between high plasma aldosterone concentrations (PACs) and diurnal blood pressure (BP) variation has not been fully elucidated. Because abnormal ambulatory blood pressure monitoring (ABPM) profiles are associated with increased CVD risk, we investigated the association between PACs and the ABPM profile in 36 patients with PA diagnosed by confirmatory tests who underwent adrenal venous sampling (AVS). The clinical parameters were measured during hospitalization for AVS. The dietary salt intake of hospitalized patients was controlled at 6 g/day. During AVS, blood samples were collected from the inferior vena cava before and 1 h after adrenocorticotropic hormone (ACTH) stimulation to measure the PACs. The post-stimulation PAC had a significant negative correlation with nocturnal BP dipping rates (R = -0.387, p = 0.020), whereas pre-stimulation PAC did not (R = -0.217, p = 0.204). The nocturnal BP dipping rates were significantly lower in the high PAC group (PAC higher than the median) than low PAC group (PAC lower than the median) (p = 0.009). Multiple regression analysis revealed that high PAC was an independent factor contributing to low nocturnal BP dipping rates (β = -0.316, p = 0.038). In conclusion, in patients with PA, hyperaldosteronism is associated with nocturnal hypertension, which is an important risk factor for CVD. Additionally, ACTH stimulation may improve the sensitivity of PACs as a clinical indicator of nocturnal hypertension.

DOI： 10.1038/s41440-023-01325-8

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記述言語：日本語   出版者・発行元：(一社)日本透析医学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals are controversial. In this study, we employed a remnant kidney mouse model as a CKD model and aimed to evaluate the effects of an HPD on kidney injury under conditions of non-CKD and CKD. Mice were divided into four groups: a sham surgery (sham) + normal diet (ND) group, a sham + HPD group, a 5/6 nephrectomy (Nx) + ND group and a 5/6 Nx + HPD group. Blood pressure, kidney function and kidney tissue injury were compared after 12 weeks of diet loading among the four groups. The 5/6 Nx groups displayed blood pressure elevation, kidney function decline, glomerular injury and tubular injury compared with the sham groups. Furthermore, an HPD exacerbated glomerular injury only in the 5/6 Nx group; however, an HPD did not cause kidney injury in the sham group. Clinical application of these results suggests that patients with CKD should follow a protein-restricted diet to prevent the exacerbation of kidney injury, while healthy individuals can maintain an HPD without worrying about the adverse effects.

DOI： 10.3390/ijms24097778

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s10157-023-02342-0

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その他リンク： https://link.springer.com/article/10.1007/s10157-023-02342-0/fulltext.html

記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ekir.2022.09.005

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Immune checkpoint inhibitors (ICIs) are becoming widely used for novel cancer treatments. Immune-related adverse events, including cardiac toxicity, are frequently observed following immune checkpoint inhibitor (ICI) use. However, little is known regarding the association between ICIs initiation and hypertension in cancer patients. METHODS: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. The risk of hypertension associated with ICI initiation in randomized controlled trials (RCTs) was evaluated. Hypertension was categorized according to the Common Terminology Criteria for Adverse Events. The odds ratios of grades I to V and grades III to V hypertension were calculated using a random-effects meta-analysis. RESULTS: Thirty-two RCTs (n=19 810 cancer patients) were included. At a median follow-up of 36 months, the median overall survival was 15 months in the ICI group. ICI initiation was not significantly associated with hypertension (grades I-V: odds ratio, 1.12 [95% CI, 0.96-1.30]; grades III-V: odds ratio, 0.95 [95% CI, 0.78-1.16]). Additionally, no significant differences in hypertension risk were evident in ICI combination therapies with various drugs, including anti-VEGF (vascular endothelial growth factor) agents. In a subgroup analysis based on clinical setting (placebo RCT versus nonplacebo RCT), there were discrepancies between the results obtained with different methodologies, with patients in the nonplacebo RCTs having higher grades I-V hypertension (I2=88.6%, P for heterogeneity=0.003). CONCLUSIONS: ICI initiation was not associated with short-term risk of hypertension in cancer patients, and the association was similar regardless of concomitant treatment with other anticancer drugs.

DOI： 10.1161/HYPERTENSIONAHA.122.19865

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.

DOI： 10.1016/j.kint.2022.01.031

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Several previous studies have suggested that uric acid-lowering therapy (ULT) can slow the progression of chronic kidney disease (CKD). Although crucial for CKD patients, few studies have evaluated the effects of different ULT medications on kidney function. This systematic review summarizes evidence from randomized controlled trials (RCTs) regarding the effects of ULT on kidney function. METHOD: We performed a systematic search of PubMed, MEDLINE, Embase, Scopus, and the Cochrane Library up to September 2021 to identify RCTs in CKD patients comparing the effects of ULT on kidney function with other ULT medications or placebo. A network meta-analysis was performed to compare each ULT indirectly. The primary outcome was a change in estimated glomerular filtration rate (eGFR) from baseline. RESULTS: Ten studies were selected with a total of 1480 patients. Topiroxostat significantly improved eGFR and reduced the urinary albumin/creatinine ratio compared to placebo (mean difference (MD) and 95% confidence interval [95% CI]: 1.49 [0.08; 2.90], P = 0.038 and 25.65% [13.25; 38.04], P < 0.001, respectively). Although febuxostat did not show a positive effect overall, it significantly improved renal function (i.e., eGFR) in a subgroup of CKD patients with hyperuricemia (MD [95% CI]: 0.85 [0.02; 1.67], P = 0.045). Allopurinol and pegloticase did not show beneficial effects. CONCLUSIONS: Topiroxostat and febuxostat may have better renoprotective effects in CKD patients than other ULT medications. Further large-scale, long-term studies are required to determine whether these effects will lead, ultimately, to reductions in dialysis induction and major adverse cardiovascular events. Key Points • This study is the first network meta-analysis comparing the nephroprotective effects of ULT in CKD patients. • Topiroxostat and febuxostat showed better renoprotective effects in CKD patients than other ULT medications. • Heterogeneity was low in this study, suggesting consistency of results.

DOI： 10.1007/s10067-021-05956-5

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記述言語：日本語   出版者・発行元：神奈川腎炎研究会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: It remains unclear which sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are most effective for preventing cardiovascular and renal events in type 2 diabetes mellitus (T2DM) patients, depending on the presence of albuminuria. We conducted a network meta-analysis to compare the efficacy of these two drug classes in T2DM patients with/without albuminuria. METHODS: We searched the Medline, EMBASE, Cochrane Library databases, and gray literature up to April 20, 2021. We included randomized controlled trials that reported the risk of major adverse cardiovascular events (MACE) and composite of renal outcomes in T2DM. RESULTS: A total of nine studies (81,206 patients) were included. In patients with/without albuminuria, SGLT-2 inhibitors did not significantly reduce the risk of MACE compared with GLP-1 RAs (risk ratio [RR] [95% confidence interval]; 0.96 [0.82-1.12] and 0.94 [0.81-1.10], respectively). In contrast, compared with GLP-1 RAs, SGLT-2 inhibitors were associated with significantly lower renal risk in both patients with/without albuminuria (RR [95% CI]; 0.75 [0.63-0.89] and 0.59 [0.44-0.79], respectively). CONCLUSIONS: SGLT-2 inhibitors may be superior to GLP-1 RAs for renal outcomes in T2DM patients with/without albuminuria, although there was no difference in the risk of MACE.

DOI： 10.1016/j.diabres.2021.109146

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Pathological activation of kidney angiotensin II (Ang II) type 1 receptor (AT1R) signaling stimulates tubular sodium transporters, including epithelial sodium channels, to increase sodium reabsorption and blood pressure. During a search for a means to functionally and selectively modulate AT1R signaling, a molecule directly interacting with the carboxyl-terminal cytoplasmic domain of AT1R was identified and named AT1R-associated protein (ATRAP/Agtrap). We showed that ATRAP promotes constitutive AT1R internalization to inhibit pathological AT1R activation in response to certain stimuli. In the kidney, ATRAP is abundantly distributed in epithelial cells along the proximal and distal tubules. Results from genetically engineered mice with modified ATRAP expression show that ATRAP plays a key role in the regulation of renal sodium handling and the modulation of blood pressure in response to pathological stimuli and further suggest that the function of kidney tubule ATRAP may be different between distal tubules and proximal tubules, implying that ATRAP is a target of interest in hypertension.

DOI： 10.1038/s41440-021-00776-1

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記述言語：英語  

Background: Tolvaptan is the gold standard treatment for autosomal dominant polycystic kidney disease (ADPKD), while several other drugs have the potential to inhibit the progression of ADPKD. However, individual clinical trials may not show sufficient differences in clinical efficacy due to small sample sizes. Furthermore, the differences in therapeutic efficacy among drugs are unclear. Herein, we investigated the effect of the ADPKD treatments. Methods: We systematically searched PubMed, Medline, EMBASE, and the Cochrane Library through January 2022 to identify randomized controlled trials in ADPKD patients that compared the effects of treatments with placebo or conventional therapy. A network meta-analysis was performed to compare the treatments indirectly. The primary outcomes were changes in kidney function and the rate of total kidney volume (TKV) growth. Results: Sixteen studies were selected with a total of 4,391 patients. Tolvaptan significantly preserved kidney function and inhibited TKV growth compared to the placebo {standardized mean difference (SMD) [95% confidence interval (CI)]: 0.24 (0.16; 0.31) and MD: -2.70 (-3.10; -2.30), respectively}. Tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors inhibited TKV growth compared to the placebo; somatostatin analogs significantly inhibited TKV growth compared to the placebo and tolvaptan [MD: -5.69 (-7.34; -4.03) and MD: -2.99 (-4.69; -1.29), respectively]. Metformin tended to preserve renal function, although it was not significant [SMD: 0.28 (-0.05; 0.61), p = 0.09]. Conclusion: The therapeutic effect of tolvaptan was reasonable as the gold standard for ADPKD treatment, while somatostatin analogs also showed notable efficacy in inhibiting TKV growth. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022300814.

DOI： 10.3389/fphar.2022.885457

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1β, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.

DOI： 10.1038/s41598-021-02864-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

DOI： 10.3390/ijms222212432

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Our previous randomized controlled trial comparing the total dose of weekly versus biweekly continuous erythropoietin receptor activator (CERA) therapy to maintain optimal hemoglobin (Hb) levels showed no significant differences between the two therapies. This post-hoc analysis assessed whether the total dose of weekly versus biweekly CERA therapy to maintain Hb levels among HD patients differed among groups with or without iron supplementation. Of 107 patients, 40 received intravenous iron supplementation due to iron deficiency (iron group) and 67 did not (non-iron group). In the iron group, the weekly therapy tended to require a lower total CERA dose compared with the biweekly therapy (274 ± 274 vs 381 ± 223 μg/12 weeks, P = 0.051). Changes in circulating hepcidin levels, a negative regulator of intestinal iron uptake, after 2 weeks of CERA treatment were significantly lower in the weekly therapy compared with the biweekly therapy (-4.2 ± 6.3 vs 11.1 ± 7.3 ng/mL, P = 0.015). In the non-iron group, there were no significant differences in total CERA dose or changes in hepcidin levels between the two therapies. Shortening the CERA treatment interval combined with iron supplementation may lead to the more efficient treatment of HD patients with iron deficiency.

DOI： 10.1016/j.jphs.2021.05.010

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Elevated angiotensin-converting enzyme 2 (ACE2) expression in organs that are potential targets of severe acute respiratory syndrome coronavirus 2 may increase the risk of coronavirus disease 2019 (COVID-19) infection. Previous reports show that ACE2 alter its tissue-specific expression patterns under various pathological conditions, including renal diseases. Here, we examined changes in pulmonary ACE2 expression in two mouse chronic kidney disease (CKD) models: adenine-induced (adenine mice) and aristolochic acid-induced (AA mice). We also investigated changes in pulmonary ACE2 expression due to renin-angiotensin system (RAS) blocker (olmesartan) treatment in these mice. Adenine mice showed significant renal functional decline and elevated blood pressure, compared with controls. AA mice also showed significant renal functional decline, compared with vehicles; blood pressure did not differ between groups. Renal ACE2 expression was significantly reduced in adenine mice and AA mice; pulmonary expression was unaffected. Olmesartan attenuated urinary albumin excretion in adenine mice, but did not affect renal or pulmonary ACE2 expression levels. The results suggest that the risk of COVID-19 infection may not be elevated in patients with CKD because of their stable pulmonary ACE2 expression. Moreover, RAS blockers can be used safely in treatment of COVID-19 patients with CKD.

DOI： 10.1038/s41598-021-96294-8

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記述言語：英語  

A 32-year-old Japanese woman at 8 weeks of gestation was admitted to our hospital for systemic edema, hypoalbuminemia, and severe proteinuria. The patient had a history of generalized alopecia and migraine. We diagnosed nephrotic syndrome, and renal biopsy revealed minimal change nephrotic syndrome (MCNS). We administered 1000 mg/day of methylprednisolone for 3 days. Oral corticosteroid therapy was followed by 40 mg of prednisolone daily. We carefully selected concomitant medication after considering organogenesis. Before and after renal biopsy, we administered heparin, antithrombin III, and immunoglobulin agents as appropriate. The patient achieved complete remission on day 8 of treatment and gave birth to a boy at 37 weeks of gestation without recurrence. MCNS during pregnancy is rare, and there is no established treatment. In conclusion, we present a case of a pregnant woman with MCNS during organogenesis. Early treatment initiation can provide a good prognosis for both mother and child.

DOI： 10.1007/s13730-020-00568-5

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patients with type 2 diabetes mellitus (T2DM) and obesity are at high risk of developing cardiovascular disease (CVD). Both glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter (SGLT-2) inhibitors have been shown to prevent CVD in T2DM patients. Additionally, the two drugs reduce body mass. However, it is unknown which drug is more effective at reducing the risk of CVD in such patients. We searched Medline, EMBASE, and Cochrane Library records to February 20, 2021 and performed a network meta-analysis to compare the efficacy with which the drugs reduced the risk of major adverse cardiovascular events (MACE). We included 102,728 patients in 12 studies containing data of obesity subgroup analyses. In T2DM patients with obesity, GLP-1 RAs significantly reduced the risk of MACE versus placebo (relative risk, RR [95% confidence interval, CI]: 0.88 [0.81-0.96]), whereas SGLT-2 inhibitors showed a tendency (RR [95% CI]: 0.91 [0.83-1.00]). In an indirect comparison, GLP-1 RAs were not associated with a significant difference in MACE compared with SGLT-2 inhibitors (RR [95% CI]: 0.97 [0.85-1.09]). Thus, GLP-1 RAs are effective at preventing MACE than placebo in T2DM patients with obesity, although further studies are warranted to conclude their superiority to SGLT-2 inhibitors.

DOI： 10.1038/s41598-021-89620-7

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記述言語：日本語   出版者・発行元：(一社)日本透析医学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Xanthine oxidoreductase (XOR) is a critical enzyme in purine metabolism and uric acid production, and its levels are reported to increase during stress, thereby promoting organ damage. Herein, we investigated the activity of XOR in a mouse model of aristolochic acid I (AA)-induced nephropathy, a type of nephrotoxic chronic kidney disease (CKD). A persistent decrease in renal function was observed in mice up to 4 weeks after 4 weeks of AA (2.5 mg kg-1 ) administration. Renal histology revealed an increase in tubular interstitial fibrosis over time. Although AA administration did not change XOR activity in the plasma, heart, liver, or muscle, XOR activity was persistently increased in renal tissue. Our results suggest that the renal tissue-specific increase in XOR activity is involved in the progression of tubulo-interstitial disorders, specifically fibrosis.

DOI： 10.1002/2211-5463.13083

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the impact of basal dietary sodium intake on the dapagliflozin-induced changes in albuminuria and blood pressure (BP) measured at home in patients with diabetic kidney disease (DKD).This was a secondary analysis of the Y-AIDA Study, in which DKD patients with estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine were administered dapagliflozin for 24 weeks, and dapagliflozin significantly improved albuminuria levels and home BP profiles. The effects on UACR, home-measured BP, and eGFR were compared between high- and low-sodium intake groups (HS and LS groups), which were created using baseline urinary sodium-to-creatinine ratio of 84 participants with available basal sodium-to-creatinine ratios. At baseline, clinic-/home-measured BPs, UACR, and eGFR, were comparable in the two groups. After 24 weeks, the reductions from baseline in ln-UACR were comparable in the two groups. In contrast, the reductions in evening home systolic BP and eGFR from baseline were larger in HS than in LS (BP: - 13 ± 2.08 vs. - 6 ± 1.88, P = 0.020; eGFR: - 3.33 ± 1.32 vs. 0.37 ± 1.29, P = 0.049). The home BP-lowering effects of dapagliflozin are larger in HS than LS, concomitant with a larger reduction in eGFR, suggesting a dapagliflozin-induced improvement in glomerular relative hyperfiltration in HS.

DOI： 10.1038/s41598-020-79687-z

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Contrast-induced acute kidney injury (CI-AKI) is a major complication after coronary angiography (CAG) or percutaneous coronary intervention (PCI) and is associated with increased morbidity and mortality. It remains controversial whether renin-angiotensin system (RAS) blockers increase or decrease CI-AKI. In this meta-analysis, we investigated the association between RAS blockers and CI-AKI in patients with normal kidney function or mild-to-moderate chronic kidney disease (CKD). MATERIALS AND METHODS: We performed a systematic search of PubMed, EMBASE, clinicaltrials.gov, and the Cochrane Library up to December 2019 for studies that assessed the association between RAS blockers and CI-AKI events after CAG/PCI. The primary outcome was the development of CI-AKI. Odds ratios (ORs) with corresponding 95% confidence interval (CI) were synthesized. RESULTS: Five randomized controlled trials (RCTs) and five observational studies were included, accounting for a total of 7,420 patients. Unstratified, RAS blocker administration was significantly associated with an increased risk of CI-AKI (pooled OR = 1.63, 95% CI 1.19 - 2.25, p = 0.003). However, the effect was not observed in RCTs (pooled OR = 1.22, 95% CI 0.54 - 2.74, p = 0.63). Sensitivity analysis in observational studies showed significant association (pooled OR = 1.77, 95% CI 1.22 - 2.55, p = 0.003) with high heterogeneity and evidence of publication bias. CONCLUSION: In patients with relatively-preserved renal function, the association of RAS blockers with an increased risk of CI-AKI after contrast media exposure was inconclusive, as sensitivity analysis showed conflicting results and bias. Although this study did not demonstrate significant evidence, it indicated that clinicians need to be vigilant in assessing the potential risk for RAS blockers to cause CI-AKI in low-risk patients.

DOI： 10.5414/CN110171

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記述言語：日本語   出版者・発行元：(一社)日本透析医学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Outcomes in acute decompensated heart failure (ADHF) have remained poor. Worsening renal function (WRF) is common among patients with ADHF. However, the impact of WRF on the prognosis is controversial. We hypothesized that in patients with ADHF, the achievement of concomitant decongestion would diminish the signal for harm associated with WRF. METHODS: We performed a systematic search of PubMed, EMBASE, and the Cochrane Library up to December 2019 for studies that assessed signs of decongestion in patients with WRF during ADHF admission. The primary outcome was all-cause mortality and heart transplantation. RESULTS: Thirteen studies were selected with a pooled population of 8138 patients. During the follow-up period of 60-450 days, 19.2% of patients died. Unstratified, patients with WRF versus no WRF had a higher risk for mortality (odds ratio [OR], 1.71 [95% confidence interval {CI}, 1.45-2.01]; P < 0.0001). However, patients who achieved decongestion had a similar prognosis (OR, 1.15 [95% CI, 0.89-1.49]; P = 0.30). Moreover, patients with WRF who achieved decongestion had a better prognosis compared with those without WRF or decongestion (OR, 0.63 [95% CI, 0.46-0.86]; P = 0.004). This tendency persisted for the sensitivity analyses. CONCLUSIONS: Decongestion is a powerful effect modifier that attenuates harmful associations of WRF with mortality. Future studies should not assess WRF as an endpoint without concomitant assessment of achieved volume status.

DOI： 10.1016/j.ekir.2020.06.031

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：神奈川県医師会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Erythropoietin-stimulating agents (ESAs) are used to treat renal anemia in patients with non-dialysis CKD, but this can lead to increases in blood pressure (BP). OBJECTIVE: We investigated the effects of continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) on office/ambulatory BP in 36 patients with non-dialysis CKD and renal anemia who did not receive ESA treatment. METHODS: Participants were randomly assigned to CERA or DA, and received ESA treatment for 24 weeks. ESA doses were adjusted to maintain hemoglobin (Hb) at 10-12 g/dL. Primary outcomes were office/ambulatory BP after 24 weeks of ESA treatment. Hb levels were within the target range at 24 weeks. RESULTS: Office/ambulatory BP, renal function, and other parameters were not significantly different between groups. However, we could not exclude the possibility that differences may exist because our sample size was small. Therefore, we also performed analysis of all of the data that were compiled from the groups of per-protocol population. Although office/ambulatory BP profiles had not worsened after 24 weeks of ESA treatment, more than half of the patients required an increase in the antihypertensive agent dose. CONCLUSIONS: CERA and DA may have similar effects on BP profiles in patients with non-dialysis CKD and renal anemia. ESA treatment often requires increases in the doses of antihypertensive agents.

DOI： 10.1159/000507396

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記述言語：日本語   出版者・発行元：神奈川県医師会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic kidney disease (CKD) progresses to end-stage renal failure via renal tubulointerstitial fibrosis. Malnutrition, inflammation, and arteriosclerosis interact to exacerbate the poor prognosis of CKD, and their effective management is thus essential. The traditional Japanese medicine Rikkunshito (RKT) exerts appetite-stimulating effects via ghrelin, which attenuates inflammation and fibrosis. We evaluated the therapeutic effect of RKT in unilateral ureter obstruction (UUO)-induced renal fibrosis/inflammation and body weight loss in mice. UUO and sham-operated mice were fed a standard diet or diet containing 3.0% RKT. Renal fibrosis was investigated by histopathology and macrophage infiltration was determined by immunohistochemistry. Expression levels of genes associated with fibrosis, inflammation, ghrelin, and mitochondrial function were determined by quantitative reverse transcription-polymerase chain reaction and western blot analyses. RKT treatment partially prevented UUO-induced weight loss but failed to attenuate renal fibrosis and inflammation. Renal expression of sirtuin 1, a ghrelin-downstream signalling molecule, and gene expression of peroxisome proliferator-activated receptor-γ coactivator 1α and Bcl-2/adenovirus E1B interacting protein 3 were unaffected by RKT. These results indicate that RKT inhibits weight loss but does not improve renal fibrosis or inflammation in a rapidly progressive renal fibrosis mouse model. RKT may have a protective effect on weight loss associated with CKD.

DOI： 10.1038/s41598-020-58214-0

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記述言語：日本語   出版者・発行元：(一社)日本内科学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The proximal tubule is a particularly important site for ageing-related kidney damage. Sirtuin 1 (SIRT1), an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase in the proximal tubule, may be involved in renal injury associated with ageing. However, the mechanisms of SIRT1 regulation remain to be elucidated. We recently reported that angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP)-deficient mice displayed age-associated renal function decline and tubulointerstitial fibrosis. Our data showed that SIRT1 protein expression was reduced in ATRAP-deficient mice, although the relationship between ATRAP deficiency and age-associated renal fibrosis is still not fully understood. It is, therefore, necessary to investigate how ATRAP affects SIRT1 protein expression to resolve ageing-associated kidney dysfunction. Here, since ageing studies are inherently lengthy, we used an ex vivo model of the proximal tubule to determine the role of ATRAP in SIRT1 protein expression. We first generated a clonal immortalised human renal proximal tubule epithelial cell line (ciRPTEC) expressing AT1R and ATRAP. Using this cell line, we demonstrated that ATRAP knockdown reduced SIRT1 protein expression in the ciRPTEC but did not alter SIRT1 mRNA expression. Thus, ATRAP likely mediates SIRT1 protein abundance in ciRPTEC.

DOI： 10.1038/s41598-019-52566-y

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記述言語：英語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The Y-AIDA study was designed to investigate the renal- and home blood pressure (BP)-modulating effects of add-on dapagliflozin treatment in Japanese individuals with type 2 diabetes mellitus (T2DM) and albuminuria. METHODS: We conducted a prospective, multicenter, single-arm study. Eighty-six patients with T2DM, HbA1c 7.0-10.0%, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min/1.73 m2, and urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine (gCr) were enrolled, and 85 of these patients were administered add-on dapagliflozin for 24 weeks. The primary and key secondary endpoints were change from baseline in the natural logarithm of UACR over 24 weeks and change in home BP profile at week 24. RESULTS: Baseline median UACR was 181.5 mg/gCr (interquartile range 47.85, 638.0). Baseline morning, evening, and nocturnal home systolic/diastolic BP was 137.6/82.7 mmHg, 136.1/79.3 mmHg, and 125.4/74.1 mmHg, respectively. After 24 weeks, the logarithm of UACR decreased by 0.37 ± 0.73 (P < 0.001). In addition, changes in morning, evening, and nocturnal home BP from baseline were as follows: morning systolic/diastolic BP - 8.32 ± 11.42/- 4.18 ± 5.91 mmHg (both P < 0.001), evening systolic/diastolic BP - 9.57 ± 12.08/- 4.48 ± 6.45 mmHg (both P < 0.001), and nocturnal systolic/diastolic BP - 2.38 ± 7.82/- 1.17 ± 5.39 mmHg (P = 0.0079 for systolic BP, P = 0.0415 for diastolic BP). Furthermore, the reduction in UACR after 24 weeks significantly correlated with an improvement in home BP profile, but not with changes in other variables, including office BP. Multivariate linear regression analysis also revealed that the change in morning home systolic BP was a significant contributor to the change in log-UACR. CONCLUSIONS: In Japanese patients with T2DM and diabetic nephropathy, dapagliflozin significantly improved albuminuria levels and the home BP profile. Improved morning home systolic BP was associated with albuminuria reduction. Trial registration The study is registered at the UMIN Clinical Trials Registry (UMIN000018930; http://www.umin.ac.jp/ctr/index-j.htm ). The study was conducted from July 1, 2015 to August 1, 2018.

DOI： 10.1186/s12933-019-0912-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The underlying pathogenesis of chronic kidney disease involves an activated renin-angiotensin system and systemic inflammation which ultimately develop renal injury. Rikkunshito (RKT) has been reported to exert anti-fibrotic and anti-inflammatory effects through enhancement of ghrelin signaling pathway. In this study, we investigated the effects of RKT on renal fibrosis and inflammation in angiotensin II (Ang II)-induced renal injury model. Ang II-infused mice exhibited hypertension, cardiac hypertrophy, increases in blood urea nitrogen and serum creatinine, moderate albuminuria and renal pathological changes such as mild urinary cast, interstitial macrophage infiltration and modest interstitial fibrosis. RKT had no evident effects on the Ang II-induced renal functional insufficiency and fibrosis, but attenuated renal interstitial macrophage infiltration. In addition, RKT significantly restored the Ang II-induced alteration in the expression of renal fibrosis- and inflammation-related genes such as type 3 collagen, transforming growth factor-β, monocyte chemoattractant protein-1 and interleukin-6. Furthermore, although RKT did not affect the expression of renal ghrelin receptor, an Ang II-induced decrease in renal sirtuin 1 expression, a critical down-stream pathway of the ghrelin receptor, was restored by RKT. These findings suggest that RKT potentially has a renal anti-inflammatory effect in the development of renal injury, and this effect could be mediated by the ghrelin signaling pathway.

DOI： 10.1038/s41598-019-42657-1

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background We have previously shown that ATRAP (angiotensin II receptor-associated protein; Agtrap) interacts with AT1R (angiotensin II type 1 receptor) and promotes constitutive internalization of AT 1R so as to inhibit hyperactivation of its downstream signaling. In response to angiotensin II , systemic ATRAP deficiency exacerbates angiotensin II -mediated hypertension via hyperactivation of renal tubular AT 1R. Although ATRAP expression is abundant in renal proximal tubules, little is known about the actual function of renal proximal tubule ATRAP in angiotensin-mediated hypertension. Methods and Results In this study, we examined the in vivo functional role of renal proximal tubule ATRAP in angiotensin-dependent hypertension. We succeeded in generating proximal tubule-specific ATRAP knockout ( PT - KO ) mice for the first time using the Cre/loxP system with Pepck-Cre. Detailed analysis of renal ATRAP expression in PT - KO mice estimated by immunohistochemical and laser-capture microdissection analysis revealed that ATRAP mRNA expression decreased by ≈80% in proximal regions of the nephron in PT - KO mice compared with wild-type ( WT ) mice. We compared blood pressure of PT - KO and WT mice using both tail-cuff and radiotelemetric methods. Blood pressure of PT - KO mice was comparable with that of WT mice at baseline. Moreover, no significant differences were noted in pressor response to angiotensin II (600 ng/kg per min or 1000 ng/kg per minute) infusion between PT - KO and WT mice. In addition, angiotensin II -mediated cardiac hypertrophy was identical between PT - KO and WT mice. Conclusions ATRAP deficiency in proximal tubules did not exacerbate angiotensin-dependent hypertension in vivo. The results indicate that renal proximal tubule ATRAP has a minor role in angiotensin-dependent hypertension in vivo.

DOI： 10.1161/JAHA.119.012395

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Enhancement of AT1 receptor-associated protein (ATRAP) in adipose tissue improves high fat diet (HFD)-induced visceral obesity and insulin resistance, and suppresses adipose oxidative stress. However, HFD loading is not a direct stimulatory factor for AT1 receptor. In the present study, we investigated the effect of chronic, low-dose angiotensin II (Ang II) stimulation on glucose and lipid metabolism in mice and functional role of ATRAP. ATRAP expression was higher in adipose tissue (5-10-fold) and skeletal muscle tissue (approximately 1.6-fold) in ATRAP transgenic (TG) mice compared with wild-type (WT) mice. After Ang II infusion, insulin sensitivity was impaired in WT mice, but this response was suppressed in TG mice. Unexpectedly, Ang II infusion did not affect the adipose tissue profile in WT or TG mice. However, in skeletal muscle tissue, Ang II stimulus caused an increase in oxidative stress and activation of p38 MAPK, resulting in a decrease in glucose transporter type 4 expression in WT mice. These responses were suppressed in TG mice. Our study suggests that Ang II-induced insulin resistance is suppressed by increased ATRAP expression in skeletal muscle tissue. Hyperactivity of AT1 receptor could be related to formation of insulin resistance related to metabolic syndrome.

DOI： 10.1038/s41598-018-21270-8

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: The components of the renin-angiotensin system in leukocytes is involved in the pathophysiology of non-communicable diseases (NCDs), including hypertension, atherosclerosis and chronic kidney disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) is an AT1R-specific binding protein, and is able to inhibit the pathological activation of AT1R signaling in certain animal models of NCDs. The aim of the present study was to investigate the expression and regulation of ATRAP in leukocytes. METHODS: Human leukocyte ATRAP mRNA was measured with droplet digital polymerase chain reaction system, and analyzed in relation to the clinical variables. We also examined the leukocyte cytokines mRNA in bone-marrow ATRAP-deficient and wild-type chimeric mice after injection of low-dose lipopolysaccharide. RESULTS: The ATRAP mRNA was abundantly expressed in leukocytes, predominantly granulocytes and monocytes, of healthy subjects. In 86 outpatients with NCDs, leukocyte ATRAP mRNA levels correlated positively with granulocyte and monocyte counts and serum C-reactive protein levels. These positive relationships remained significant even after adjustment. Furthermore, the leukocyte ATRAP mRNA was significantly associated with the interleukin-1β, tumor necrosis factor-α and monocyte chemotactic protein-1 mRNA levels in leukocytes of NCDs patients. In addition, the leukocyte interleukin-1β mRNA level was significantly upregulated in bone marrow ATRAP-deficient chimeric mice in comparison to wild-type chimeric mice after injection of lipopolysaccharide. CONCLUSIONS: These results suggest that leukocyte ATRAP is an emerging marker capable of reflecting the systemic and leukocyte inflammatory profile, and plays a role as an anti-inflammatory factor in the pathophysiology of NCDs.

DOI： 10.1016/j.atherosclerosis.2018.01.013

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Abnormal angiogenesis plays a major role in the development of early stage diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a classical proangiogenic factor that regulates abnormal glomerular angiogenesis linked to glomerular hypertrophy in the early stage of diabetic nephropathy. Leucine-rich α-2-glycoprotein-1 (LRG1) was recently reported as a novel proangiogenic factor that is expressed in endothelial cells and promotes angiogenesis by modulating the transforming growth factor-β signaling pathway. However, the pathophysiology of LRG1 in diabetic nephropathy remains largely unknown. In the present study, we investigated intrarenal expression of the novel proangiogenic factor LRG1 in diabetic db/db mice by immunohistochemistry and a laser capture microdissection method during the development of diabetic nephropathy. We hypothesized that glomerular LRG1 expression is increased earlier than VEGF expression under conditions of pathological angiogenesis in the early stage of diabetic nephropathy. Thus, we compared glomerular expression of VEGF and LRG1 in diabetic db/db mice at 16 and 24 weeks of age. At 16 weeks, diabetic db/db mice exhibited glomerular hypertrophy with abnormal angiogenesis characterized by endothelial cell proliferation, which was concomitant with an increase in LRG1 expression of glomerular endothelial cells. However, glomerular VEGF expression was not increased at this early stage. At 24 weeks, the features of early diabetic nephropathy in db/db mice had developed further, along with further enhanced glomerular LRG1 expression. At this late stage, glomerular VEGF and fibrosis-related-gene expression was also significantly increased compared with nondiabetic db/m mice. These results suggest that LRG1 plays a pivotal role in the initial development of diabetic nephropathy by promoting abnormal angiogenesis, thereby suggesting that LRG1 is a potential preemptive therapeutic target of diabetic nephropathy.

DOI： 10.1155/2018/2817045

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The kidney is easily affected by aging-associated changes, including glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Particularly, renal tubulointerstitial fibrosis is a final common pathway in most forms of progressive renal disease. Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP), which was originally identified as a molecule that binds to AT1R, is highly expressed in the kidney. Previously, we have shown that ATRAP suppresses hyperactivation of AT1R signaling, but does not affect physiological AT1R signaling. METHODS AND RESULTS: We hypothesized that ATRAP has a novel functional role in the physiological age-degenerative process, independent of modulation of AT1R signaling. ATRAP-knockout mice were used to study the functional involvement of ATRAP in the aging. ATRAP-knockout mice exhibit a normal age-associated appearance without any evident alterations in physiological parameters, including blood pressure and cardiovascular and metabolic phenotypes. However, in ATRAP-knockout mice compared with wild-type mice, the following takes place: (1) age-associated renal function decline and tubulointerstitial fibrosis are more enhanced; (2) renal tubular mitochondrial abnormalities and subsequent increases in the production of reactive oxygen species are more advanced; and (3) life span is 18.4% shorter (median life span, 100.4 versus 123.1 weeks). As a key mechanism, age-related pathological changes in the kidney of ATRAP-knockout mice correlated with decreased expression of the prosurvival gene, Sirtuin1. On the other hand, chronic angiotensin II infusion did not affect renal sirtuin1 expression in wild-type mice. CONCLUSIONS: These results indicate that ATRAP plays an important role in inhibiting kidney aging, possibly through sirtuin1-mediated mechanism independent of blocking AT1R signaling, and further protecting normal life span.

DOI： 10.1161/JAHA.117.006120

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Angiotensin II type 1 receptor-associated protein (ATRAP) promotes AT1R internalization along with suppression of hyperactivation of tissue AT1R signaling. Here, we provide evidence that renal ATRAP plays a critical role in suppressing hypertension in a mouse remnant kidney model of chronic kidney disease. The effect of 5/6 nephrectomy on endogenous ATRAP expression was examined in the kidney of C57BL/6 and 129/Sv mice. While 129/Sv mice with a remnant kidney showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that downregulation of renal ATRAP expression is involved in pathogenesis of hypertension in the remnant kidney model of chronic kidney disease. Interestingly, 5/6 nephrectomy in ATRAP-knockout mice on the hypertension-resistant C57BL/6 background caused hypertension with increased plasma volume. Moreover, in knockout compared to wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel α-subunit and tumor necrosis factor-α was significantly enhanced, concomitant with increased plasma membrane angiotensin II type 1 receptor in the kidneys. Thus, renal ATRAP downregulation is involved in the onset and progression of blood pressure elevation caused by renal mass reduction, and implicates ATRAP as a therapeutic target for hypertension in chronic kidney disease.

DOI： 10.1016/j.kint.2016.10.035

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Activation of tissue renin-angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAPfl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAPadipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAPfl/fl mice, ATRAPadipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAPfl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAPadipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders.

DOI： 10.3390/ijms18030676

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The renin-angiotensin system has a pivotal role in the pathophysiology of visceral obesity. Angiotensin II type 1 receptor (AT1R) is a major player in the signal transduction of the renin-angiotensin system, and the overactivation of this signaling contributes to the progression of visceral obesity. We have shown that the AT1R-associated protein (ATRAP) promotes AT1R internalization from the cell surface into cytoplasm along with the suppression of overactivation of tissue AT1R signaling. In this study, we examined whether the enhancement of adipose ATRAP expression could efficiently prevent diet-induced visceral obesity and insulin resistance. METHODS AND RESULTS: We generated adipocyte-specific ATRAP transgenic mice using a 5.4-kb adiponectin promoter, and transgenic mice and littermate control mice were fed either a low- or high-fat diet for 10 weeks. Although the physiological phenotypes of the transgenic and control mice fed a low-fat diet were comparable, the transgenic mice exhibited significant protection against high-fat diet-induced adiposity, adipocyte hypertrophy, and insulin resistance concomitant with an attenuation of adipose inflammation, macrophage infiltration, and adipokine dysregulation. In addition, when mice were fed a high-fat diet, the adipose expression of glucose transporter type 4 was significantly elevated and the level of adipose phospho-p38 mitogen-activated protein kinase was significantly attenuated in the transgenic mice compared with control mice. CONCLUSIONS: Results presented in this study suggested that the enhancement in adipose ATRAP plays a protective role against the development of diet-induced visceral obesity and insulin resistance through improvement of adipose inflammation and function via the suppression of overactivation of adipose AT1R signaling. Consequently, adipose tissue ATRAP is suggested to be an effective therapeutic target for the treatment of visceral obesity.

DOI： 10.1161/JAHA.116.004488

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

UNLABELLED: As there may be an association between within-visit blood pressure (BP) variability and cardiovascular disease (CVD), we investigated the clinical significance of this BP variability in non-dialysis chronic kidney disease (CKD) patients. MATERIALS AND METHODS: According to the median of coefficient of variation (CV) of three systolic BP (SBP) readings within a single visit, we divided hypertensive patients with stage G1-4 CKD already treated with antihypertensive therapy into the high SBP-CV group and the low SBP-CV group. Univariate and multivariate linear regression analyses were also performed to explore the contributing factors to within-visit BP variability. RESULTS: In the high SBP-CV group, the clinic BP, total cholesterol level, dyslipidemia, and past history of CVD were significantly greater, while α1-blockers and renin-angiotensin system (RAS) inhibitors usage were significantly reduced compared with the lower SBP-CV group. Within-visit BP variability was significantly and positively correlated with total cholesterol (R = 0.392, P < 0.001) and low-density lipoprotein cholesterol (R = 0.284, P = 0.013). Total cholesterol (β = 0.269, P = 0.024), α1-blockers usage (β = -0.260, P = 0.015), and RAS inhibitors usage (β = -0.266, P = 0.017) were shown to independently contribute to the within-visit BP variability after adjustment for age, sex, presence of diabetes, CVD history, statins usage, and clinic SBP. CONCLUSIONS: We show that within-visit BP variability may be a clinically relevant factor of CVD risk, and lipid lowering and/or anti-hypertensive therapies using RAS inhibitors and α1-blockers may be associated with the improved within-visit BP variability observed in non-dialysis CKD patients.

DOI： 10.1080/10641963.2017.1313850

PubMed

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We examined the efficacy of single-pill irbesartan/amlodipine combination-based therapy for 12 weeks in 20 hypertensive chronic kidney disease (CKD) patients, by evaluating self-measured home blood pressure (BP) profile. The single-pill irbesartan/amlodipine combination-based therapy decreased clinic BP and home BP (morning, evening, and nighttime BPs), and improved within-visit clinic BP variability, day-by-day home BP variability (morning and evening), and nighttime home BP variability. Furthermore, the single-pill combination-based therapy reduced albuminuria and exerted improved parameters of vascular function. These results indicate that this single-pill combination-based therapy may exert beneficial effects on clinic and home BP profiles as well as on renal and vascular damages, in hypertension with CKD.

DOI： 10.1080/10641963.2016.1200063

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We compared the therapeutic effects of aliskiren (direct renin inhibitor (DRI) group) with angiotensin II (Ang II) type 1 receptor blockers (ARBs) (ARB group) on clinic blood pressure (BP) and ambulatory BP in 36 hypertensive chronic kidney disease (CKD) patients. The baseline clinic BP levels and the after-treatment/baseline (A/B) ratios of clinic BP levels, estimated after 24-week treatment period, were similar in DRI group (n = 18) and ARB group (n = 18). With respect to the effects on ambulatory BP, the A/B ratios of the daytime and nighttime systolic BP in DRI group were significantly higher than those in ARB group. The A/B ratio of ankle-brachial pressure index after the study was higher in the DRI group compared with the ARB group. The results of the present study suggest that DRI therapy is not superior to ARB therapy in lowering ambulatory BP in hypertensive CKD patients, in spite of comparable clinic BP-lowering effects.

DOI： 10.1080/10641963.2016.1200064

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In non-dialysis chronic kidney disease (CKD) patients with dyslipidemia, statin therapy is recommended to prevent cardiovascular complications. Dyslipidemia has been also shown to be an independent risk factor for the progression of CKD. However, it is still unclear whether statin therapy exerts an inhibitory effect on renal deterioration in CKD patients with dyslipidemia. The purpose of the present study was to examine possible therapeutic effects of statin add-on therapy on renal function as well as parameters of lipid and glucose metabolism, arterial stiffness and oxidative stress, in comparison to diet therapy, in CKD patients with dyslipidemia. METHODS: This study was a randomized, open-label, and parallel-group trial consisted of a 12-months treatment period in non-dialysis CKD patients with alubuminuria and dyslipidemia. Twenty eight patients were randomly assigned either to receive diet counseling alone (diet therapy group) or diet counseling plus pitavastatin (diet-plus-statin therapy group), to achieve the LDL-cholesterol (LDL-C) target of <100 mg/dl. RESULTS: The statin treatment by pitavastatin was well tolerated in all of the patients without any significant adverse events and the average dose of pitavastatin was 1.0 ± 0.0 mg daily after treatment. After the 12-months treatment period, LDL-C was significantly lower in the diet-plus-statin therapy group compared with the diet therapy group (diet vs diet-plus-statin: LDL-C, 126 ± 5 vs 83 ± 4 mg/dL, P < 0.001). On the other hand, the diet-plus-statin therapy did not significantly reduce albuminuria or delay the decline in eGFR compared with the diet therapy, and there was no relationship between the change in LDL-C and the change in eGFR or albuminuria. However, diet therapy as well as diet-plus-statin therapy exerted similar lowering effects on the pentosidine levels (diet therapy group, baseline vs 12 months: 40 ± 4 vs 24 ± 3 ng/mL, P = 0.001; diet-plus-statin therapy, 46 ± 7 vs 34 ± 6 ng/mL, P = 0.008). Furthermore, the results of multivariate regression analysis indicated that the change in pentosidine was a significant contributor to the change in eGFR (β = -0.536, P = 0.011). CONCLUSIONS: Although statin add-on therapy did not show additive renal protective effects, the diet therapy as well as the diet-plus-statin therapy could contribute to the reduction in plasma pentosidine in CKD patients with albuminuria and dyslipidemia.

DOI： 10.1186/s12944-015-0164-5

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BENTHAM SCIENCE PUBL LTD  

Exaggerated activation of the renin-angiotensin system via tissue angiotensin II (Ang II) type 1 receptor (AT1R) signaling exerts detrimental effects on cardiovascular, renal and endocrine systems to provoke hypertension and related target organ damage. On the other hand, accumulated research evidence of both basic and clinical studies shows that physiological AT1R signaling also plays an indispensable role for the normal organ development such as the kidney and the maintenance of cardiovascular and renal homeostasis. Such functional diversity of AT1R signaling prompts us to seek a new strategy of selective modulation of AT1R signaling in pathophysiology. In the course of an investigational search for a means to functionally and selectively modulate AT1R signaling for that purpose, a molecule directly interacting with the carboxyl-terminal cytoplasmic domain of AT1R was identified by employing yeast two-hybrid screening of a mouse kidney cDNA library and named AT1R-associated protein (ATRAP). The results of functional analysis showed that ATRAP promotes constitutive AT1R internalization in cultured cells and inhibits Ang II-mediated pathological response in mouse distal convoluted cells. The ATRAP is expressed in a variety of tissues including the kidney where ATRAP is abundantly distributed in epithelial cells along the renal tubules. The results employing genetic engineered mice with modified ATRAP expression showed that ATRAP plays a key role in the regulation of renal sodium handling and the modulation of blood pressure in response to pathological stimuli such as chronic Ang II infusion, and suggest ATRAP to be a target of interest.

DOI： 10.2174/0929867322666150821095036

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：英語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(株)先端医学社  

国内における末期腎不全透析患者は先進諸国の中で最も多いとされ、CKDを中心とする腎疾患対策は重要な課題である。腎臓は血圧調節において中心的な役割を担う臓器であるために、腎疾患では血圧異常を伴うことが多く、また、腎疾患診療における適切な血圧管理は腎障害の進行と心腎連関による脳心血管合併症の予防のために極めて重要である。CKD患者も対象に含まれた米国のSPRINT研究の結果を受けて、CKDでの血圧管理において、「厳格降圧」による脳心血管病(全死亡)の抑制重視の方針、あるいは「標準降圧」による末期腎不全(透析導入・腎移植)の抑制重視の方針のどちらの選択をとるのかという議論になりがちである。しかし、診察室血圧はガイドラインでは重要であるが、実際の診療では診察室血圧測定以上に診察室外血圧(家庭血圧、自由行動下血圧)測定による血圧変動指標を参照しての「降圧の質」を向上させる個別的な血圧管理が重要となる。(著者抄録)

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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記述言語：日本語   出版者・発行元：日本ベーリンガーインゲルハイム(株)  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(NPO)日本高血圧学会  

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記述言語：日本語   出版者・発行元：(株)医学出版  

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2015306382

記述言語：日本語   出版者・発行元：(NPO)日本急性血液浄化学会  

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記述言語：日本語   出版者・発行元：(一社)日本透析医学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：OXFORD UNIV PRESS  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本腎臓学会  

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