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：英語   掲載種別：研究論文（学術雑誌）  

A 74-year-old Japanese male with lung squamous cell carcinoma received his first dose of immune checkpoint inhibitors (ICIs): ipilimumab and nivolumab. He developed acute kidney injury (AKI) and was admitted to our department. We diagnosed kidney immune-related adverse effects (irAE), and a kidney biopsy revealed acute tubulointerstitial nephritis. We started oral prednisolone (PSL) and his AKI immediately improved. The patient maintained stable findings after PSL was tapered off. However, seven months after the ICI administration, he developed rapid progressive glomerular nephritis and was admitted to our department again. The second kidney biopsy showed findings consistent with anti-glomerular basement membrane glomerulonephritis. Although the patient was treated with pulse methylprednisolone followed by oral PSL and plasma exchange, he became dependent on maintenance hemodialysis. To our knowledge, no case report has described two different types of biopsy-proven nephritis. In cases of suspected relapsing kidney irAEs, both a relapse of previous nephritis and the development of another type of nephritis should be considered.

DOI： 10.1007/s13730-024-00855-5

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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：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：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：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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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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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）  

AIMS: Both sodium-glucose cotransporter-2 (SGLT-2) inhibitors and mineralocorticoid receptor antagonists (MRAs) have been shown to reduce cardiovascular (CV) event in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). However, little evidence pertains to the benefits of their combined use. METHODS: We systematically searched the PubMed, MEDLINE, EMBASE, and Cochrane Library databases through July 2022. We selected randomized controlled trials comparing SGLT-2 inhibitors, MRAs, or SGLT-2 inhibitor + MRA combination therapy, with placebo in patients with T2D and CKD. We performed a network meta-analysis to indirectly compare the treatments. The primary outcome was a composite of CV events. RESULTS: Eight studies were selected with 36,186 patients. The primary outcome was significantly improved in the combination therapy group compared with the other groups (RR [95% CI]; vs SGLT-2 inhibitors, 0.76 [0.60; 0.96]; vs MRAs, 0.66 [0.53; 0.82]; vs placebo, 0.58 [0.47; 0.73]). Additionally, the combination therapy was associated with a considerable reduction in the risk of hyperkalemia (RR vs MRA, 0.43 [0.23; 0.79]). CONCLUSION: Combination of SGLT-2 inhibitors and MRAs potentially reduced CV events compared with SGLT-2 inhibitors or MRAs alone. This combination may be a candidate treatment strategy for patients with T2D and CKD.

DOI： 10.1016/j.diabres.2022.110161

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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：日本語   出版者・発行元：(一社)日本臨床腎移植学会  

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記述言語：日本語   出版者・発行元：(一社)日本アフェレシス学会  

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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）  

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）  

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：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：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：(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：(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：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：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）  

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

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1155/2018/2817045

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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

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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

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 cc-subunit and tumor necrosis factor-alpha 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

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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

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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：WILEY  

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 mitogenactivated 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

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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：TAYLOR & FRANCIS INC  

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 alpha(1)-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 &lt; 0.001) and low-density lipoprotein cholesterol (R = 0.284, P = 0.013). Total cholesterol (beta= 0.269, P = 0.024), a(1)-blockers usage (beta= -0.260, P = 0.015), and RAS inhibitors usage (beta= -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 alpha(1)-blockers may be associated with the improved within-visit BP variability observed in non-dialysis CKD patients.

DOI： 10.1080/10641963.2017.1313850

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/hr.2016.71

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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）   出版者・発行元：TAYLOR & FRANCIS INC  

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

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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：TAYLOR & FRANCIS INC  

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

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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：BIOMED CENTRAL LTD  

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 &lt;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 &lt; 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 (beta = -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

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/hr.2015.65

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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：ELSEVIER IRELAND LTD  

Objective: There is no clinical evidence that supports the benefit of integrative medicine, defined as combination therapy of oriental and western medicine, on obesity-related hypertension. This study evaluates the efficacy of Bofu-tsusho-san (BOF), an oriental herbal medicine, on the ambulatory blood pressure (BP) profile in hypertensive patients with obesity.
Methods: The study design was a multicenter, randomized, open-label, parallel-group controlled trial in 107 hypertensive patients with obesity. Participants were randomly assigned to receive either the conventional control therapy or BOF add-on therapy. In both groups antihypertensive therapy was aimed at achieving the target clinic BP. The primary outcome was change in the ambulatory BP profile from baseline to 24 weeks after randomization.
Results: Daytime systolic BP variability, an important parameter of ambulatory BP profile, was decreased in the BOF group, and the difference in the changes in daytime systolic BP variability was significant between the BOF and control group (Control vs BOF; the change from baseline in daytime systolic BP variability, 1.0 +/- 3.3 vs -1.0 +/- 3.3%; p = 0.006).
Conclusion: The BOF add-on therapy effectively improved the ambulatory BP variability. This is the first report suggesting that an integrative medicine approach may exert favorable effects on obesity-related hypertension compared with conventional pharmaceutical treatment. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.

DOI： 10.1016/j.atherosclerosis.2015.01.025

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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：WILEY-BLACKWELL  

Background-Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP; Agtrap gene) promotes AT1R internalization along with suppression of pathological AT1R activation. In this study, we examined whether enhancement of ATRAP in the renal distal tubules affects sodium handling and blood pressure regulation in response to high salt (HS) loading, using ATRAP transgenic mice on a salt-sensitive C57BL/6J background.
Methods and Results-Renal ATRAP transgenic (rATRAP-Tg) mice, which exhibit renal tubule-dominant ATRAP enhancement, and their wild-type littermate C57BL/6J mice on a normal salt diet (0.3% NaCl) at baseline were subjected to dietary HS loading (4% NaCl) for 7 days. In rATRAP-Tg mice, the dietary HS loading-mediated blood pressure elevation was suppressed compared with wild-type mice, despite similar baseline blood pressure. Although renal angiotensin II level was comparable in rATRAP-Tg and wild-type mice with and without HS loading, urinary sodium excretion in response to HS loading was significantly enhanced in the rATRAP-Tg mice. In addition, functional transport activity of the amiloride-sensitive epithelial Na+ channel was significantly decreased under saline volume-expanded conditions in rATRAP-Tg mice compared with wild-type mice, without any evident change in epithelial Na+ channel protein expression. Plasma membrane AT1R expression in the kidney of rATRAP-Tg mice was decreased compared with wild-type mice.
Conclusions-These results demonstrated that distal tubule-dominant enhancement of ATRAP inhibits pathological renal sodium reabsorption and blood pressure elevation in response to HS loading. The findings suggest that ATRAP-mediated modulation of sodium handling in renal distal tubules could be a target of interest in salt-sensitive blood pressure regulation.

DOI： 10.1161/JAHA.114.001594

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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

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/hr.2014.130

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記述言語：日本語   出版者・発行元：南江堂  

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その他リンク： http://search.jamas.or.jp/link/ui/2015008973

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP) promotes AT1R internalization along with suppression of pathological activation of tissue AT1R signaling. However, the functional significance of ATRAP in renal sodium handling and blood pressure regulation under pathological stimuli is not fully resolved. Here we show the blood pressure of mice with a gene-targeted disruption of ATRAP was comparable to that of wild-type mice at baseline. However, in ATRAP-knockout mice, angiotensin II-induced hypertension was exacerbated and the extent of positive sodium balance was increased by angiotensin II. Renal expression of the sodium-proton antiporter 3, a major sodium transporter in the proximal tubules, urinary pH, renal angiotensinogen production, and angiotensin II content was unaffected. Stimulation of the renal expression and activity of the epithelial sodium channel (ENaC), a major sodium transporter in the distal tubules, was significantly enhanced by chronic angiotensin II infusion. The circulating and urinary aldosterone levels were comparable. The blood pressure response and renal ENaC expression by aldosterone were not affected. Thus, ATRAP deficiency exacerbated angiotensin II-mediated hypertension by pathological activation of renal tubular AT1R by angiotensin II. This directly stimulates ENaC in the distal tubules and enhances sodium retention in an aldosterone-independent manner.

DOI： 10.1038/ki.2014.95

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記述言語：英語   出版者・発行元：NATURE PUBLISHING GROUP  

DOI： 10.1038/hr.2014.105

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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：HINDAWI PUBLISHING CORPORATION  

In the present study, we examined the therapeutic effects of olmesartan, an angiotensin II (Ang II) type 1 receptor (AT1R)-specific blocker, in genetically obese diabetic KKAy mice, a model of human metabolic disorders with visceral obesity, with a focus on an olmesartan effect on the adipose tissue. Olmesartan treatment (3mg/kg per day) for 4 weeks significantly lowered systolic blood pressure but did not affect body weight during the study period in KKAy mice. However, there were three interesting findings possibly related to the pleiotropic effects of olmesartan on adipose tissue in KKAy mice: (1) an inhibitory effect on adipocyte hypertrophy, (2) a suppressive effect on IL-6 gene expression, and (3) an ameliorating effect on oxidative stress. On the other hand, olmesartan exerted no evident influence on the adipose tissue expression of AT1R-associated protein (ATRAP), which is a molecule interacting with AT1R so as to inhibit pathological AT1R activation and is suggested to be an emerging molecular target in metabolic disorders with visceral obesity. Collectively, these results suggest that the blood pressure lowering effect of olmesartan in KKAy mice is associated with an improvement in adipocyte, including suppression of adipocyte hypertrophy and inhibition of the adipose IL-6-oxidative stress axis. Further study is needed to clarify the functional role of adipose ATRAP in the pleiotropic effects of olmesartan.

DOI： 10.1155/2014/946492

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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：IVYSPRING INT PUBL  

Recent studies indicate that the functional renin-angiotensin system (RAS) exists in the adipose tissue. The adipose tissue RAS is proposed in the pathophysiology of metabolic disorders. In the present study, we examined therapeutic effects of irbesartan, an angiotensin II (Ang II) type 1 receptor (AT1R)-specific blocker, in genetically obese diabetic KKAy mice, a model of human metabolic disorders without any dietary loading, with our focus on the analysis on possible effect of irbesartan on the adipose tissue. The treatment with irbesartan significantly lowered systolic blood pressure with a concomitant decrease in body weight in KKAy mice. In addition, irbesartan significantly decreased the adipose leptin mRNA expression and tended to decrease IL-6 mRNA expression in the adipose tissue of KKAy mice. Furthermore irbesartan preserved the adipose gene expression of AT1R-associated protein (ATRAP), an endogenous inhibitory molecule of tissue AT1R signaling, with a concomitant tendency of up-regulation of adipose tissue ATRAP/AT1R ratio. Collectively, these results suggest that the irbesartan-induced beneficial suppressive effect on the leptin-IL-6 axis in the adipose tissue in KKAy mice is partly mediated by a trend of up-regulation of the adipose ATRAP/AT1R ratio as one of pleiotropic effects of irbesartan.

DOI： 10.7150/ijms.8577

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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：HINDAWI PUBLISHING CORPORATION  

Both strict blood pressure (BP) control and improvements in BP profile such as BP variability are important for suppression of renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In the present study, we examined the beneficial effects of the single pill-based combination therapy of amlodipine and atorvastatin on achievement of the target BP and clinic BP profile, as well as markers of vascular and renal damages in twenty hypertensive CKD patients. The combination therapy with amlodipine and atorvastatin for 16 weeks significantly decreased clinic BP, and achievement of target BP control was attained in an average of 45% after the combination therapy in spite of the presence of no achievement at baseline. In addition, the combination therapy significantly decreased the within-visit BP variability. With respect to the effects on renal damage markers, combination therapy with amlodipine and atorvastatin for 16 weeks significantly decreased albuminuria (urine albumin-to-creatinine ratio, 1034 +/- 1480 versus 733 +/- 1218 mg/g-Cr, P &lt; 0.05) without decline in estimated glomerular filtration rate. Concerning parameters of vascular function, the combination therapy significantly improved both brachial-ankle pulse wave velocity (baPWV) and central systolic BP (cSBP) (baPWV, 1903 perpendicular to 353 versus 1786 perpendicular to 382 cm/s, P &lt; 0.05; cSBP, 148 perpendicular to 19 versus 129 +/- 23 mmHg, P &lt; 0.01). Collectively, these results suggest that the combination therapy with amlodipine and atorvastatin may exert additional beneficial effects on renal and vascular damages as well as BP profile in addition to BP lowering in hypertension with CKD.

DOI： 10.1155/2014/437087

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Aims: Activation of tissue angiotensin II (Ang II) type 1 receptor (AT1R) plays an important role in the development of vascular remodelling. We have shown that the AT1R-associated protein (ATRAP/Agtrap), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent pathological activation of the tissue renin-angiotensin system. In this study, we investigated the effects of ATRAP on Ang II-induced vascular remodelling. Methods and results: Transgenic (Tg) mice with a pattern of aortic vascular-dominant overexpression of ATRAP were obtained, and Ang II or vehicle was continuously infused into Tg and wild-type (Wt) mice via an osmotic minipump for 14 days. Although blood pressure of Ang II-infused Tg mice was comparable with that of Ang II-infused Wt mice, the Ang II-mediated development of aortic vascular hypertrophy was partially inhibited in Tg mice compared with Wt mice. In addition, Ang II-mediated up-regulation of vascular Nox4 and p22 pox, NADPH oxidase components, and 4-HNE, a marker of reactive oxygen species (ROS) generation, was significantly suppressed in Tg mice, with a concomitant inhibition of activation of aortic vascular p38MAPKand JNKby Ang II. This protection afforded by vascular ATRAP against Ang II-induced activation of NADPH oxidase is supported by in vitro experimental data using adenoviral transfer of recombinant ATRAP. Conclusion: These results indicate that activation of aortic vascular ATRAP partially inhibits the Nox4/p22 phox-ROS-p38MAPK/JNK pathway and pathological aortic hypertrophy provokedby Ang II-mediated hypertension, thereby suggesting ATRAPasa novel receptor-binding modulator of vascular pathophysiology. © The Author 2013.

DOI： 10.1093/cvr/cvt225

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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：PUBLIC LIBRARY SCIENCE  

Accumulating evidence indicates that metabolic dysfunction with visceral obesity is a major medical problem associated with the development of hypertension, type 2 diabetes (T2DM) and dyslipidemia, and ultimately severe cardiovascular and renal disease. Therefore, an effective anti-obesity treatment with a concomitant improvement in metabolic profile is important for the treatment of metabolic dysfunction with visceral obesity. Bofu-tsu-shosan (BOF) is one of oriental herbal medicine and is clinically available to treat obesity in Japan. Although BOF is a candidate as a novel therapeutic strategy to improve metabolic dysfunction with obesity, the mechanism of its beneficial effect is not fully elucidated. Here, we investigated mechanism of therapeutic effects of BOF on KKAy mice, a model of human metabolic disorders with obesity. Chronic treatment of KKAy mice with BOF persistently decreased food intake, body weight gain, low-density lipoprotein cholesterol and systolic blood pressure. In addition, both tissue weight and cell size of white adipose tissue (WAT) were decreased, with concomitant increases in the expression of adiponectin and peroxisome proliferator-activated receptors genes in WAT as well as the circulating adiponectin level by BOF treatment. Furthermore, gene expression of uncoupling protein-1, a thermogenesis factor, in brown adipose tissue and rectal temperature were both elevated by BOF. Intriguingly, plasma acylated-ghrelin, an active form of orexigenic hormone, and short-term food intake were significantly decreased by single bolus administration of BOF. These results indicate that BOF exerts a combinatorial favorable metabolic modulation including antihypertensive effect, at least partially, via its beneficial effect on adipose tissue function and its appetite-inhibitory property through suppression on the ghrelin system.

DOI： 10.1371/journal.pone.0075560

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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：MDPI AG  

An altered ambulatory blood pressure (BP) and heart rate (HR) profile is related to chronic kidney disease (CKD) and cardiorenal syndrome. In this study, we examined the effects of aliskiren, when added to angiotensin II type 1 receptor blockers, on ambulatory BP and cardiorenal function in CKD. Thirty-six hypertensive CKD patients were randomly assigned to the aliskiren add-on group (n = 18) or the benazepril add-on group (n = 18). Ambulatory BP and cardiorenal function parameters were measured at baseline and 24 weeks after treatment. Compared with the benazepril group, nighttime systolic BP variability in the aliskiren group was lower after treatment. Albuminuria was decreased in the aliskiren group, but not in the benazepril group. In addition, left ventricular mass index (LVMI) was significantly lower in the aliskiren group than in the benazepril group after treatment. In the aliskiren group, multivariate linear regression analysis showed an association between changes in albuminuria and changes in nighttime systolic BP. Furthermore, there were associations between changes in LVMI and changes in daytime HR variability, as well as between changes in LVMI and changes in plasma aldosterone concentration. These results suggest that aliskiren add-on therapy may be beneficial for suppression of renal deterioration and pathological cardiac remodeling through an improvement that is effected in ambulatory BP and HR profiles.

DOI： 10.3390/ijms140815361

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Ambulatory blood pressure (BP) and heart rate (HR) profile are proposed to be related to renal deterioration and cardiovascular complication in hypertension and chronic kidney disease (CKD). In this study, we examined the beneficial effects cilnidipine, a unique L/N-type calcium channel blocker (CCB), in addition to renin-angiotensin system inhibitors, on ambulatory BP and HR profile, as well as cardiorenal function in hypertensive CKD patients. Forty-five patients were randomly assigned to the cilnidipine replacement group (n = 21) or the control CCBs group (n = 24) during a 24-week active treatment period. Although clinical BP values were similar in the cilnidipine and control CCBs groups after the treatment period, the results of ambulatory BP monitoring showed that the 24-h and daytime systolic BP levels in the cilnidipine group were significantly lower compared with the control group after the study. Furthermore, the left ventricular mass index (LVMI) was significantly decreased in the cilnidipine group compared to the control group after the study (LVMI, 135.3 ± 26.4 versus 181.2 ± 88.4, p = 0.031), with a significant difference in the changes in the LVMI between the cilnidipine and control groups (change in LVMI, -12.4 ± 23.7 versus 26.2 ± 64.4, p = 0.007). These results indicate that cilnidipine is beneficial for the suppression of pathological cardiac remodeling, at least partly, via a superior improving effect on ambulatory BP profile compared with control CCBs in hypertensive CKD patients. © 2013 by the authors
licensee MDPI, Basel, Switzerland.

DOI： 10.3390/ijms140816866

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

In July 2003, a 63-year-old man received a low anterior resection for rectal cancer. In February 2006, he underwent a right hepatectomy for a solitary metastatic liver tumor
the liver tumor had not invaded the bile duct, and a curative resection was performed. In August 2008, an enhanced computed tomography examination revealed a massive focal lesion at the point of the common bile duct. Endoscopic ultrasonography clearly revealed a hyperechoic polypoid lesion that had spread laterally on the surface of the slightly dilated bile duct and had a smooth outer hyperechoic layer. No lymph nodes were present in this region. Endoscopic retrograde cholangiopancreatography revealed an irregular stricture, and a biopsy was performed through the scope. Microscopic examination revealed a tumor characterized as a moderately differentiated adenocarcinoma resembling the liver tumor. We diagnosed the intrabiliary tumor as a metachronous metastatic bile duct tumor from rectal cancer without involvement of the liver parenchyma. This is a very rare case, with recurrence only in an extrahepatic bile duct after the complete resection of a metastatic liver tumor. This is the first clinical, pathological, and radiological description of this rare condition. © Springer 2011.

DOI： 10.1007/s12328-011-0240-y

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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：(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：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：(一社)和漢医薬学会  

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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)和漢医薬学会  

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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：日本語   出版者・発行元：(株)南江堂  

＜文献概要＞・慢性腎臓病(CKD)患者は末期腎不全の予備軍であり,かつ心血管系疾患の合併高リスクである.近年では65歳以上の高齢者の末期腎不全患者の増加傾向がみられる.・高齢CKD患者の治療に関するエビデンスは限られているが,75歳以上の後期高齢者における,包括的治療管理による末期腎不全への進展,重症合併症阻止,QOLの維持・向上を図ることの意義は大きいと考えられる.・CKD患者に対する包括的な管理は,新規透析導入の抑制のみならず,患者の生命予後や生活の質の改善にも寄与できると考えられる.・健常な高齢者においても加齢に伴い腎機能は徐々に低下していくが,最近高齢者において増加傾向のCKDステージG3以降になると,腎予備能の低下に対する残存ネフロンの代償機能が保てなくなり,高血圧,体液過剰,電解質異常がみられるようになる.・さらに腎性貧血,慢性腎臓病に伴う骨・ミネラル代謝異常(CKD-MBD),代謝性アシドーシスが出現してくる.・こうした症候に一つ一つ対処することで,症候の改善だけでなく腎機能低下の抑制効果,心血管疾患の発症予防も期待される.

DOI： 10.15106/j_naika121_867

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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：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：(一社)日本内科学会  

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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：(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：(有)フジメディカル出版  

慢性腎臓病(CKD)における血圧管理では、病態[糖尿病合併・蛋白尿(アルブミン尿)合併の有無、推算糸球体濾過量(eGFR)低下の程度]に応じた個別的な血圧管理(降圧目標、降圧薬選択)が推奨されている。糖尿病合併CKDでの降圧目標は、診察室血圧130/80mmHg未満。糖尿病非合併CKDでは、蛋白尿ありの場合(A2、A3区分)は130/80mmHg未満、蛋白尿なしの場合(A1区分)は140/90mmHg未満が降圧目標である。最近では、厳格な降圧が求められるCKDを合併した高血圧患者における高齢者の割合が増加しており、まず年齢による降圧目標(65〜74歳の降圧目標:140/90mmHg未満、75歳以上の降圧目標:150/90mmHg未満)が優先されている。さらに忍容性があれば、合併症の存在による低いほうの降圧目標(糖尿病合併CKD・高血圧の場合、糖尿病非合併CKDで蛋白尿・アルブミン尿を有する場合に130/80mmHg未満)を目指して緩徐に降圧を図ることが推奨されている。後期高齢者を含む、心血管リスクを伴う高血圧でのSPRINT研究の結果では、厳格降圧治療(目標収縮期血圧120mmHg未満)により、標準降圧治療(目標収縮期血圧140mmHg未満)に比較して複合心血管イベント、死亡率の減少が報告されたが、CKDにおける意義についてはさらなる検討が必要である。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J06106&link_issn=&doc_id=20170724120002&doc_link_id=%2Fal1jikod%2F2017%2F000603%2F003%2F0126-0134%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fal1jikod%2F2017%2F000603%2F003%2F0126-0134%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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：(株)先端医学社  

現在慢性腎臓病(CKD)は、初期の腎障害である微量アルブミン尿から腎臓の障害が進んだ末期腎不全までを含める病態である。わが国のCKD患者は、成人で約1,330万人、つまり成人の8人に1人が発症するとされる。とくにCKDの初期では尿検査上アルブミン尿を呈するものの症状に乏しく、早期診断と早期治療介入が重要である。CKDの原因は、慢性糸球体腎炎や多発性嚢胞腎など固有腎疾患の場合と、糖尿病、高血圧、高尿酸血症(痛風)、内臓脂肪型肥満(メタボリックシンドローム)など、いわゆる生活習慣病の場合に大別される。最近では、透析療法あるいは腎移植が必要な末期腎不全の原疾患として、生活習慣病が原因の糖尿病性腎症や腎硬化症が増加傾向を示しており、CKD対策を講じるうえで生活習慣病対策の重要性が増加しているのが現状である。CKDに対する治療としては、(1)生活習慣の改善、(2)食事療法、(3)薬物療法が3本柱であり、併存することが多い生活習慣病、およびCKD合併症(腎性貧血、骨・ミネラル代謝異常、高カリウム血症・代謝性アシドーシスなど)に対する多面的な治療の必要性からどうしても処方薬剤数が多くなり服薬アドヒアランス上の問題が生じることも多い。この点、合剤は服用薬剤数減少を介した服薬アドヒアランス改善による治療効果の向上が報告されており、CKD治療上、とくに重要とされる血圧管理においても合剤の意義が今後大きくなっていくと考えられる。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)先端医学社  

現在慢性腎臓病(CKD)は、初期の腎障害である微量アルブミン尿から腎臓の障害が進んだ末期腎不全までを含める病態である。わが国のCKD患者は、成人で約1,330万人、つまり成人の8人に1人が発症するとされる。とくにCKDの初期では尿検査上アルブミン尿を呈するものの症状に乏しく、早期診断と早期治療介入が重要である。CKDの原因は、慢性糸球体腎炎や多発性嚢胞腎など固有腎疾患の場合と、糖尿病、高血圧、高尿酸血症(痛風)、内臓脂肪型肥満(メタボリックシンドローム)など、いわゆる生活習慣病の場合に大別される。最近では、透析療法あるいは腎移植が必要な末期腎不全の原疾患として、生活習慣病が原因の糖尿病性腎症や腎硬化症が増加傾向を示しており、CKD対策を講じるうえで生活習慣病対策の重要性が増加しているのが現状である。CKDに対する治療としては、(1)生活習慣の改善、(2)食事療法、(3)薬物療法が3本柱であり、併存することが多い生活習慣病、およびCKD合併症(腎性貧血、骨・ミネラル代謝異常、高カリウム血症・代謝性アシドーシスなど)に対する多面的な治療の必要性からどうしても処方薬剤数が多くなり服薬アドヒアランス上の問題が生じることも多い。この点、合剤は服用薬剤数減少を介した服薬アドヒアランス改善による治療効果の向上が報告されており、CKD治療上、とくに重要とされる血圧管理においても合剤の意義が今後大きくなっていくと考えられる。(著者抄録)

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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)総合医学社  

＜Point＞CKDでは、CKD CGA重症度分類に基づく、病態[糖尿病合併・蛋白尿(アルブミン尿)合併の有無、eGFR低下の程度]に応じた個別的な血圧管理(降圧目標、降圧薬選択)が重要である。日本腎臓学会の「エビデンスに基づくCKD診療ガイドライン2013」、日本高血圧学会の「高血圧治療ガイドラインJSH2014」は上記の方針に従って作成されており、CKDでの血圧管理に有用である。糖尿病合併CKDでの血圧管理における降圧目標は、日本に多い脳卒中抑制効果のエビデンスも重視して130/80mmHg未満に設定されている。糖尿病非合併CKDでは、蛋白尿あり(A2、A3区分)の場合は、主に腎保護のエビデンスから130/80mmHg未満が降圧目標とされた一方、蛋白尿なし(A1区分)の場合は140/90mmHg未満が降圧目標として設定されている。心血管リスクを伴う高血圧でのSPRINT研究の結果では、厳格降圧治療(目標収縮期血圧120mmHg未満)により、標準降圧治療(目標収縮期血圧140mmHg未満)に比較して複合心血管イベント、死亡率の減少が報告されたが、CKDにおける意義についてはさらなる解析が必要である。(著者抄録)

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記述言語：日本語  

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：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：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：(株)東京医学社  

54歳女。巣状分節状糸球体性硬化症による末期腎不全のため、CAPDカテーテル留置術をSMAP法で施行した。腹膜透析導入目的で入院した。出口部作製術を施行し、腹膜透析液の貯留を開始したところ、乾性咳嗽および右胸部圧迫感を自覚した。胸部X線で右胸水貯留を認め、99mTc-MAAシンチグラフィで右横隔膜交通症と診断した。交通部位同定法に色素注入法を用いて右胸腔鏡下横隔膜縫縮術を施行した。術後4日目から腹膜透析を開始した。胸水貯留のないことを確認し、軽快退院した。退院4ヵ月後、乾性咳嗽および左胸水貯留を認め、再入院した。99mTc-MAAシンチグラフィで左横隔膜交通症と診断した。腹膜透析継続を希望したため、左胸腔鏡下横隔膜縫縮術を施行した。術後5日目から腹膜透析を開始した。胸水貯留のないことを確認し、退院した。術後1年経過した現在、再発を認めず、腹膜透析を継続している。

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記述言語：日本語   出版者・発行元：(株)日本臨床社  

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記述言語：日本語   出版者・発行元：(株)先端医学社  

JNC8では、CKD合併高血圧・糖尿病合併高血圧における降圧目標をともに140/90mmHg未満としている。また、降圧薬の第一選択薬については、CKD合併高血圧ではRA系阻害薬(ACE阻害薬、ARB)、糖尿病合併高血圧ではサイアザイド系利尿薬、RA系阻害薬、Ca拮抗薬(非黒人)、あるいはサイアザイド系利尿薬、Ca拮抗薬(黒人)が推奨されている。これらJNC8での推奨内容には、JSH2014との間に相違点が複数認められる。(著者抄録)

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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：WILEY-BLACKWELL  

Web of Science

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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：日本語   出版者・発行元：(株)ライフメディコム  

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記述言語：日本語   出版者・発行元：日本心脈管作動物質学会  

1型アンジオテンシンII(AT1受容体)に結合する新規因子(AT1 receptor-associated protein:ATRAP/Agtrap)の単離同定と構造解析、ATRAP/Agtrapの組織分布、ATRAP/AgtrapによるAT1受容体のinternalization促進作用、血管平滑筋細胞(VSMC)におけるATRAP/Agtrapの機能、生体におけるATRAP/Agtrapの発現調節の検討、血管壁を含む生体におけるATRAP/Agtrapの機能、ATRAP/Agtrapの発現・活性制御機構の検討について述べた。

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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：日本語   出版者・発行元：(一社)日本透析医学会  

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