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

A regulatory mechanism for SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule, is incompletely understood. Here, we report an important regulation of SLC family transporter by SETD2, a chromatin remodeling gene whose alterations have been found in a subset of kidney cancers. Kidney-specific inactivation of Setd2 resulted in hypovolemia with excessive urine excretion in mouse and interestingly, RNA-sequencing analysis of Setd2-deficient murine kidney exhibited decreased expressions of SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule. Importantly, inactivation of Setd2 in murine kidney displayed attenuated dapagliflozin-induced diuresis and glucose excretion, further supporting that SETD2 might regulate SLCfamily transporter-mediated sodium and glucose reabsorptions in renal tubule. These data uncover an important regulation of SLC family transporter by SETD2, which may illuminate a crosstalk between metabolism and epigenome in renal tubule.

DOI： 10.1016/j.bbrc.2024.150730

PubMed

researchmap

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

Objective Patients undergoing maintenance dialysis are at a higher risk of morbidity and mortality due to severe coronavirus disease 2019 (COVID-19) than the general population. However, longitudinal data regarding this subpopulation of patients are lacking. We therefore examined the prognosis of patients with COVID-19 undergoing maintenance dialysis between 2020 and 2023. In addition, we explored the factors correlated with COVID-19 severity, focusing on the transition thereof throughout the observational period. Methods The primary outcome was the progression to severe or fatal COVID-19. We evaluated the correlation between the primary outcome and baseline demographic and clinical characteristics of patients. Patients undergoing maintenance dialysis who were hospitalized for mild-to-moderate COVID-19 between February 2020 and April 2023 were enrolled at four institutions in Kanagawa, Japan. Results Of the 173 patients, 7 (4.0%) developed severe COVID-19, and 12 (6.9%) died. The severe/death cohort was significantly older, with a higher percentage of unvaccinated patients than the non-severe cohort (58.2% and 25.0%, respectively; p=0.016). Thymus and activation-regulated chemokine levels on admission were lower in the severe/death cohort than in the non-severe cohort, albeit not to a statistically significant degree (148±84 mg/dL and 342±657 pg/mL, respectively; p=0.082). A multivariate logistic regression analysis revealed that the odds ratio for severe morbidity or death was 0.23 (95% confidence interval: 0.07-0.75) for vaccinated patients. Conclusion In patients undergoing maintenance dialysis, the severity rate of COVID-19 is approximately 10%. Vaccination was correlated with a reduced risk of severe COVID-19.

DOI： 10.2169/internalmedicine.4199-24

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

The renin-angiotensin system (RAS) plays a crucial role in the regulation of blood pressure. Activation of the angiotensin II (Ang II)-Ang II type 1 receptor (AT1R) signaling pathway contributes to the pathogenesis of hypertension and subsequent organ damage. AT1R-associated protein (ATRAP) has been identified as an endogenous inhibitory protein of the AT1R pathological activation. We have shown that mouse Atrap (Atrap) represses various Ang II-AT1R-mediated pathologies, including hypertension in mice. The expression of human ATRAP (ATRAP) /Atrap can be altered in various pathological states in humans and mice, such as Ang II stimulation and serum starvation. However, the regulatory mechanisms of ATRAP/Atrap are not yet fully elucidated. MicroRNAs (miRNAs) are 21-23 nucleotides of small RNAs which post-transcriptionally repress gene expression. Single miRNA can act on hundreds of target mRNAs, and numerous miRNAs have been identified as the Ang II-AT1R signaling-associated disease phenotype modulator, but nothing is known about the regulation of ATRAP/Atrap. In the present study, we identified miR-125a-5p and miR-125b-5p as the evolutionarily conserved miRNAs that potentially act on ATRAP/Atrap mRNA. Further analysis revealed that miR-125a-5p and miR-125b-5p can directly repress both ATRAP and Atrap. In addition, the inhibition of miR-125a-5p/miR-125b-5p resulted in the suppression of the Ang II-AT1R signaling in mouse distal convoluted tubule (mDCT) cells. Taken together, miR-125a-5p/miR-125b-5p activates Ang II-AT1R signaling by the suppression of ATRAP/Atrap. Our results provide new insights into the potential approaches for achieving the organ-protective effects by the repression of the miR-125 family associated with the enhancement of ATRAP/Atrap expression.

DOI： 10.1016/j.jbc.2023.105478

PubMed

researchmap

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

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

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-023-01508-3

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

Diabetic nephropathy (DN) is characterized by abnormal kidney energy metabolism, but its causes and contributions to DN pathogenesis are not clear. To examine this issue, we carried out targeted metabolomics profiling in a mouse model of DN that develops kidney disease resembling the human disorder. We found a distinct profile of increased lactate levels and impaired energy metabolism in kidneys of mice with DN, and treatment with an angiotensin-receptor blocker (ARB) reduced albuminuria, attenuated kidney pathology and corrected many metabolic abnormalities, restoring levels of lactate toward normal while increasing kidney ATP content. We also found enhanced expression of lactate dehydrogenase isoforms in DN. Expression of both the LdhA and LdhB isoforms were significantly increased in kidneys of mice, and treatment with ARB significantly reduced their expression. Single-cell sequencing studies showed specific up-regulation of LdhA in the proximal tubule, along with enhanced expression of oxidative stress pathways. There was a significant correlation between albuminuria and lactate in mice, and also in a Southeast Asian patient cohort consisting of individuals with type 2 diabetes and impaired kidney function. In the individuals with diabetes, this association was independent of ARB and angiotensin-converting enzyme inhibitor use. Furthermore, urinary lactate levels predicted the clinical outcomes of doubling of serum creatinine or development of kidney failure, and there was a significant correlation between urinary lactate levels and biomarkers of tubular injury and epithelial stress. Thus, we suggest that kidney metabolic disruptions leading to enhanced generation of lactate contribute to the pathogenesis of DN and increased urinary lactate levels may be a potential biomarker for risk of kidney disease progression.

DOI： 10.1016/j.kint.2023.08.006

PubMed

researchmap

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

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

PubMed

researchmap

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

AIMS: Diabetes mellitus (DM) is the leading cause of chronic kidney disease. Albuminuria is associated with an increased risk of cardiovascular mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) and mineralocorticoid receptor antagonists (MRAs) protect against albuminuria; however, their combined effects on albuminuria are unclear. We performed a network meta-analysis to investigate the effects of SGLT2-Is, MRAs and their combination on albuminuria in type 2 DM. METHODS: We systematically searched PubMed, Medline, EMBASE and the Cochrane Library from inception up to 20 November 2022. We selected randomized control and crossover trials that compared MRAs, SGLT2-Is, MRAs + SGLT2-Is, or a placebo in patients with type 2 DM with a urinary albumin-creatinine ratio (UACR) ≥30 mg/g creatinine. The primary outcome was the change in the UACR. RESULTS: This meta-analysis analysed 17 studies with 34 412 patients. The use of combination treatment with SGLT2-Is and MRAs was associated with lower albuminuria compared with the use of SGLT2-Is, MRAs, or the placebo alone [mean difference (95% CI): -34.19 (-27.30; -41.08), -32.25 (-24.53; -39.97) and -65.22 (-57.97; -72.47), respectively]. Treatment with SGLT2-Is or MRAs alone caused a significant reduction in UACR compared with the placebo [mean difference (95% CI): -31.03 (-28.35; -33.72) and -32.97 (-29.68; -36.27), respectively]. The effects of MRAs on the UACR are comparable with those of SGLT2-Is. Sensitivity analyses showed similar results. CONCLUSION: Combination therapy with SGLT2-Is and MRAs was associated with lower albuminuria in patients with type 2 DM compared with monotherapy with SGLT2-Is or MRAs alone.

DOI： 10.1111/dom.14976

PubMed

researchmap

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

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

PubMed

researchmap

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

The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor-neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin-angiotensin system inhibitors (RAS-Is) in large clinical trials such as the PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS-Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM-HF trial, ARNI was associated with more albuminuria compared with RAS-I; thus, it is unclear whether long-term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS-I in patients with chronic kidney disease in the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS-I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.

DOI： 10.1161/JAHA.122.029565

PubMed

researchmap

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

DOI： 10.1007/s10157-023-02342-0

researchmap

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

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

DOI： 10.1016/j.ekir.2022.09.005

PubMed

researchmap

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

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

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-022-01106-9

PubMed

researchmap

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

Kidney fibrosis is a common pathway that leads to chronic kidney disease. Angiotensin II type-1 receptor (AT1R)-associated protein (ATRAP) was originally identified as an AT1R-binding protein. Previously, we reported that systemic knockout of ATRAP exacerbates kidney fibrosis in aged mice. Although these effects of ATRAP appeared to be AT1R-independent actions, the molecular mechanism remains poorly understood. To elucidate the molecular mechanism of ATRAP independent of AT1R, we explored novel ATRAP-interacting proteins. Mass spectrometric analysis of the immunoprecipitants of a Flag-tagged ATRAP complex revealed 376 candidate proteins that potentially interact with ATRAP. Gene ontology analysis revealed that proteins related to vesicle trafficking, membrane transport, and many membrane proteins, including transferrin receptor 1 (TfR1), were enriched. Because TfR1 promotes cellular iron uptake and iron is a key factor involved in kidney fibrosis, we focused on TfR1 and confirmed that it interacts with ATRAP. In addition, our findings revealed that enhanced ATRAP expression decreased cell-surface TfR1 expression without altering the overall cellular TfR1 expression levels. Furthermore, enhanced ATRAP expression attenuated cellular iron levels. Together, our results highlight the role of ATRAP as a suppressor of TfR1 that functions by facilitating TfR1 internalization, which affects iron metabolism and oxidative stress signaling.

DOI： 10.1038/s41598-022-22343-5

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

Language：English  

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

PubMed

researchmap

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

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

DOI： 10.3390/ijms23010302

PubMed

researchmap

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

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

PubMed

researchmap

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

INTRODUCTION: The erythropoietin resistance index (ERI) is an indicator of erythropoiesis-stimulating agent (ESA) responsiveness and is typically calculated using Hb. However, Hb does not directly reflect ESA-induced erythropoiesis because of its long-term nature. We thus designed a novel ERI calculated with reticulocyte Hb (RetHb), a real-time index, and investigated its association with mortality in HD patients. METHODS: We calculated the ERI using the change in RetHb before and after ESA administration (ERIΔRetHb ) and retrospectively analyzed its association with 3-year all-cause mortality using Kaplan-Meier survival curves and Cox regression analyses. RESULTS: A total of 102 patients were included. Patients with the highest ERIΔRetHb had the worst prognosis according to the Kaplan-Meier survival curves (Log-rank p = 0.02). Multivariate Cox regression analysis showed that the ERIΔRetHb was significantly and independently associated with all-cause mortality (hazard ratio: 9.82, 95% CI [1.50, 64.41], p = 0.02). CONCLUSION: The ERIΔRetHb was significantly and independently associated with all-cause mortality in HD patients.

DOI： 10.1111/1744-9987.13772

PubMed

researchmap

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

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

PubMed

researchmap

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

To explore the biological and immunological basis of human rheumatoid arthritis and human atherosclerosis, we planned and reported a detailed design and rationale for Orencia Atherosclerosis and Rheumatoid Arthritis Study (ORACLE Arthritis Study) using highly sensitive, high-throughput, human autoantibody measurement methods with cell-free protein synthesis technologies. Our previous study revealed that subjects with atherosclerosis had various autoantibodies in their sera, and the titers of anti-Th2 cytokine antibodies were correlated with the severity of atherosclerosis. Because rheumatoid arthritis is a representative autoimmune disease, we hypothesized that both rheumatoid arthritis and atherosclerosis are commonly developed by autoantibody-mediated autoimmune processes, leading to incessant inflammatory changes in both articular joint tissues and vessel walls. We planned a detailed examination involving carotid artery ultrasonography, measurements of adhesion molecules, such as ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) for the evaluation of atherosclerosis progression, and high-throughput, high-sensitivity, autoantibody analyses using cell-free technologies, with detailed examinations of the disease activity of rheumatoid arthritis. Analyses of correlations and associations between biological markers and degrees of carotid atherosclerosis over time under consistent conditions may enable us to understand the biological and humoral immunity background of human atherosclerosis and autoimmune diseases.

DOI： 10.3390/mps4040083

PubMed

researchmap

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

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, and 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 (82,206 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

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

Although continuous erythropoietin receptor activators (CERAs) are widely used erythropoiesis-stimulating agents for correcting renal anemia in patients undergoing hemodialysis (HD), few reports have examined weekly CERA administration. In this randomized controlled trial, we compared the efficacy and changes in the parameters of iron metabolism and erythropoiesis between weekly and biweekly CERA administration. In total, 120 patients undergoing maintenance HD were randomized to the weekly or biweekly group. The primary end point was the total CERA dose needed to maintain the target hemoglobin (Hb) levels during a 12-week evaluation period. There was no significant difference in the total dose between the weekly and biweekly groups (median 175.0 [interquartile range (IQR) 93.8-337.5] µg/12 weeks vs. 300.0 [IQR 125.0-375.0] µg/12 weeks, P = .18). The mean Hb levels during the evaluation period were 10.9 ± 0.8 g/dL in the weekly group and 10.7 ± 0.8 g/dL in the biweekly group (P = .25). Weekly CERA administration was well tolerated. Weekly CERA administration similarly managed anemia as biweekly administration in patients undergoing HD.

DOI： 10.1111/jch.14171

PubMed

researchmap

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

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

PubMed

researchmap

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

BACKGROUND: Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients. METHODS: We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized. RESULTS: Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75-0.96] and 0.68 [0.59-0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80-1.04] and 0.86 [0.72-1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78-1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63-0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69-0.95]), while exendin-4 analogues did not (RR 1.03 [0.88-1.20]). CONCLUSIONS: In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

DOI： 10.1186/s12933-020-01197-z

PubMed

researchmap

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

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

PubMed

researchmap

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

A novel approach is required for standard therapy-resistant peripheral arterial disease (PAD). This is a single-center, single-arm, interventional study (LDL Apheresis-Mediated Endothelial Activation Therapy to Severe-Peripheral Artery Disease study), which aims to evaluate the efficacy and safety of lipoprotein apheresis (LA) with a dextran sulfate cellulose column in PAD with controlled serum cholesterol levels. The study participants have standard therapy-resistant PAD with controlled serum cholesterol levels. A total of 35 patients undergo 10 sessions of LA therapy. The ankle-brachial index and vascular quality of life questionnaire are assessed before and after the treatment period as primary outcomes. Registration of patients began in November 2015 and is planned to be concluded in October 2020.

DOI： 10.1111/1744-9987.13546

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

Language：English  

DOI： 10.1038/s41440-019-0381-9

PubMed

researchmap

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

PURPOSE OF REVIEW: The renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating blood pressure and body fluid, which contributes to the pathophysiology of hypertension and cardiovascular/renal diseases. However, accumulating evidence has further revealed the complexity of this signal transduction system, including direct interactions with other receptors and proteins. This review focuses on recent research advances in RAAS with an emphasis on its receptors. RECENT FINDINGS: Both systemically and locally produced angiotensin II (Ang II) bind to Ang II type 1 receptor (AT1R) and elicit strong biological functions. Recent studies have shown that Ang II-induced activation of Ang II type 2 receptor (AT2R) elicits the opposite functions to those of AT1R. However, accumulating evidence has now expanded the components of RAAS, including (pro)renin receptor, angiotensin-converting enzyme 2, angiotensin 1-7, and Mas receptor. In addition, the signal transductions of AT1R and AT2R are regulated by not only Ang II but also its receptor-associated proteins such as AT1R-associated protein and AT2R-interacting protein. Recent studies have indicated that inappropriate activation of local mineralocorticoid receptor contributes to cardiovascular and renal tissue injuries through aldosterone-dependent and -independent mechanisms. Since the mechanisms of RAAS signal transduction still remain to be elucidated, further investigations are necessary to explore novel molecular mechanisms of the RAAS, which will provide alternative therapeutic agents other than existing RAAS blockers.

DOI： 10.1007/s11906-020-1028-6

PubMed

researchmap

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

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

PubMed

researchmap

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

Background: Both native T1 time and extracellular volume (ECV) fraction have been shown to be important measures for the detection of myocardial fibrosis. However, ECV determination requires the administration of an intravenous contrast agent, whereas native T1 mapping can be performed without a contrast agent. Methods: Here, we conducted a meta-analysis of myocardial native T1 data obtained for non-ischemic cardiomyopathy (NIC) patients and controls. A literature review included studies that applied T1 mapping using modified Look-Locker inversion recovery to measure myocardial fibrosis, and the results were validated by comparing datasets for dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM) patients and healthy controls (HCs). Results: We identified 16 eligible studies. Pooled mean differences (MDs) and 95% confidence intervals (CIs) were estimated as follows. Native T1 at 1.5-T, DCM vs. HC: MD = 45.26 (95% CI: 30.92-59.59); HCM vs. HC: MD = 47.09 (95% CI: 32.42-61.76). Native T1 at 3.0-T, DCM vs. HC: MD = 82.52 (95% CI: 47.60-117.44); HCM vs. HC: MD = 115.87 (95% CI: 50.71-181.04). ECV at 1.5-T, DCM vs. HC: MD = 4.26 (95% CI: 3.06-5.46); HCM vs. HC: MD = 1.49 (95% CI: -1.45-4.43). ECV at 3.0-T, DCM vs. HC: MD = 8.40 (95% CI: 2.94-13.86); HCM vs. HC: MD = 8.02 (95% CI: 5.45-1-0.59). Conclusion: In conclusion, native T1 values were significantly different between NIC patients and controls. Native T1 mapping may be a useful noninvasive method to detect diffuse myocardial fibrosis in NIC patients.

DOI： 10.1016/j.ijcha.2019.100422

PubMed

researchmap

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

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

PubMed

researchmap

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

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

PubMed

researchmap

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

DOI： 10.1038/s41598-019-42657-1

Web of Science

PubMed

researchmap

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

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

PubMed

researchmap

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

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide, but its molecular pathogenesis is not well defined, and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. In this study, we describe a mouse model combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension, and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy; the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice early in the course of their disease. We find dramatic differences in regulation of immune and inflammatory pathways, with upregulation of proinflammatory pathways in the susceptible (129) strain and coordinate downregulation in the resistant (C57BL/6) strain. Many of these pathways are also upregulated in rat models and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and RAS activation, may be critical early determinants of susceptibility to DN.

DOI： 10.2337/db17-1323

PubMed

researchmap

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

DOI： 10.1111/jch.13274

PubMed

researchmap

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

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

researchmap

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

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

researchmap

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

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in the developed world. Accordingly, an urgent need exists for new, curative treatments as well as for biomarkers to stratify risk of DN among individuals with diabetes mellitus. A barrier to progress in these areas has been a lack of animal models that faithfully replicate the main features of human DN. Such models could be used to define the pathogenesis, identify drug targets and test new therapies. Owing to their tractability for genetic manipulation, mice are widely used to model human diseases, including DN. Questions have been raised, however, about the general utility of mouse models in human drug discovery. Standard mouse models of diabetes typically manifest only modest kidney abnormalities, whereas accelerated models, induced by superimposing genetic stressors, recapitulate key features of human DN. Incorporation of systems biology approaches and emerging data from genomics and metabolomics studies should enable further model refinement. Here, we discuss the current status of mouse models for DN, their limitations and opportunities for improvement. We emphasize that future efforts should focus on generating robust models that reproduce the major clinical and molecular phenotypes of human DN.

DOI： 10.1038/nrneph.2017.142

PubMed

researchmap

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

DOI： 10.1155/2018/2817045

Web of Science

PubMed

researchmap

Language：English  

DOI： 10.1016/j.atherosclerosis.2017.08.018

PubMed

researchmap

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

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

researchmap

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

We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr). Both ion channels have also been shown to bind to Nedd4-2 via a conserved Proline-Tyrosine (PY) motif in C-terminal with subsequent ubiquitination and degradation by proteasome. Therefore, loss of Nedd4-2 C2 isoform might be involved in electrophysiological impairment under various conditions. We demonstrate here that Nedd4-2 C2 isoform causes cardiac conduction change in resting condition as well as proarrhythmic change after acute myocardial infarction (MI). The Nedd4-2 C2 knockout (KO) mice showed bradycardia, prolonged QRS, QT intervals, and suppressed PR interval in resting condition. In addition, enhancement of T peak/T end interval was found in mice with surgical ligation of the distal left coronary artery. Morphological analyses based on both ultrasonography of the living heart, as well as histopathological findings revealed that Nedd4-2 C2 KO mice show no significant structural changes from wild-type littermates under resting conditions. These results suggested that Nedd4-2 with C2 domain might play an important role in cardio-renal syndrome through post-transcriptional modification of both ENaC and cardiac ion channels, which are critical for kidney and heart functions.

DOI： 10.3390/ijms18061268

PubMed

researchmap

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

DOI： 10.3390/ijms18061250

Web of Science

PubMed

researchmap

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

Plasma membrane calcium pump isoform 1 (PMCA1) is encoded by ATPase plasma membrane Ca2+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

PubMed

researchmap

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

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

researchmap

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

DOI： 10.3390/ijms18030676

Web of Science

PubMed

researchmap

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

DOI： 10.1161/JAHA.116.004488

Web of Science

PubMed

researchmap

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

DOI： 10.1080/10641963.2017.1313850

Web of Science

PubMed

researchmap

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

DOI： 10.1038/hr.2016.71

PubMed

researchmap

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

DOI： 10.21037/jtd.2016.05.10

PubMed

researchmap

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

DOI： 10.1038/hr.2016.1

PubMed

researchmap

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

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

researchmap

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

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

researchmap

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

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

researchmap

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

DOI： 10.1038/hr.2015.60

PubMed

researchmap

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

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. CLINICAL TRIAL REGISTRATION: UMIN000003878.

DOI： 10.1016/j.atherosclerosis.2015.01.025

PubMed

researchmap

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

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

PubMed

researchmap

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

DOI： 10.2174/0929867322666150821095036

Web of Science

researchmap

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

DOI： 10.1038/hr.2014.130

PubMed

researchmap

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

DOI： 10.1038/hr.2014.105

PubMed

researchmap

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

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

PubMed

researchmap

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

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 (3 mg/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

PubMed

researchmap

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

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 < 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 ± 353 versus 1786 ± 382 cm/s, P < 0.05; cSBP, 148 ± 19 versus 129 ± 23 mmHg, P < 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

PubMed

researchmap

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

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

PubMed

researchmap

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

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(phox), 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 p38MAPK and JNK by 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 provoked by Ang II-mediated hypertension, thereby suggesting ATRAP as a novel receptor-binding modulator of vascular pathophysiology.

DOI： 10.1093/cvr/cvt225

PubMed

researchmap

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

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.

DOI： 10.3390/ijms140816866

PubMed

researchmap

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

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

DOI： 10.1161/JAHA.113.000312

PubMed

researchmap

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

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

PubMed

researchmap

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

The angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP/Agtrap) promotes constitutive internalization of the AT1R so as to specifically inhibit the pathological activation of its downstream signaling yet preserve the base-line physiological signaling activity of the AT1R. Thus, tissue-specific regulation of Agtrap expression is relevant to the pathophysiology of cardiovascular and renal disease. However, the regulatory mechanism of Agtrap gene expression has not yet been fully elucidated. In this study, we show that the proximal promoter region from -150 to +72 of the mouse Agtrap promoter, which contains the X-box, E-box, and GC-box consensus motifs, is able to elicit substantial transcription of the Agtrap gene. Among these binding motifs, we showed that the E-box specifically binds upstream stimulatory factor (Usf) 1 and Usf2, which are known E-box-binding transcription factors. It is indicated that the E-box-Usf1/Usf2 binding regulates Agtrap expression because of the following: 1) mutation of the E-box to prevent Usf1/Usf2 binding reduces Agtrap promoter activity; 2) knockdown of Usf1 or Usf2 affects both endogenous Agtrap mRNA and Agtrap protein expression, and 3) the decrease in Agtrap mRNA expression in the afflicted kidney by unilateral ureteral obstruction is accompanied by changes in Usf1 and Usf2 mRNA. Furthermore, the results of siRNA transfection in mouse distal convoluted tubule cells and those of unilateral ureteral obstruction in the afflicted mouse kidney suggest that Usf1 decreases but Usf2 increases the Agtrap gene expression by binding to the E-box. The results also demonstrate a functional E-box-USF1/USF2 interaction in the human AGTRAP promoter, thereby suggesting that a strategy of modulating the E-box-USF1/USF2 binding has novel therapeutic potential.

DOI： 10.1074/jbc.M113.451054

PubMed

researchmap

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

We have previously shown that angiotensin II type 1 receptor-associated protein (ATRAP/Agtrap) interacts with the angiotensin II type 1 receptor and promotes constitutive internalization of the receptor so as to inhibit the pathological activation of its downstream signaling but preserve baseline physiological signaling activity. The present study was designed to investigate the role of renal ATRAP in angiotensin II-dependent hypertension. We generated transgenic mice dominantly expressing ATRAP in the renal tubules, including renal distal tubules. The renal ATRAP transgenic mice exhibited no significant change in blood pressure at baseline on normal salt diet. However, in the renal ATRAP transgenic mice compared with wild-type mice, the following took place: (1) the development of high blood pressure in response to angiotensin II infusion was significantly suppressed based on radiotelemetry, (2) the extent of daily positive sodium balance was significantly reduced during angiotensin II infusion in metabolic cage analysis, and (3) the renal Na+ -Cl- cotransporter activation and α-subunit of the epithelial sodium channel induction by angiotensin II infusion were inhibited. Furthermore, adenoviral overexpression of ATRAP suppressed the angiotensin II-mediated increase in the expression of α-subunit of the epithelial sodium channel in mouse distal convoluted tubule cells. These results indicate that renal tubule-dominant ATRAP activation provokes no evident effects on blood pressure at baseline but exerts an inhibitory effect on the pathological elevation of blood pressure in response to angiotensin II stimulation, thereby suggesting that ATRAP is a potential target of interest in blood pressure modulation under pathological conditions.

DOI： 10.1161/HYPERTENSIONAHA.111.00572

PubMed

researchmap

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

Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD). Patients with CKD are reported to have a significant greater risk of CVD-associated mortality than that of the general population after stratification for age, gender, race, and the presence or absence of diabetes. CKD itself is also an independent risk factor for the development of atherosclerosis, and in particular, patients undergoing dialysis typically bear many of the risk factors for atherosclerosis, such as hypertension, dyslipidemia and disturbed calcium-phosphate metabolism, and commonly suffer from severe atherosclerosis, including peripheral arterial disease (PAD). Low-density lipoprotein (LDL) apheresis is a potentially valuable treatment applied to conventional therapy-resistant hypercholesterolemic patients with coronary artery disease and PAD. Although previous and recent studies have suggested that LDL apheresis exerts beneficial effects on the peripheral circulation in dialysis patients suffering from PAD, probably through a reduction of not only serum lipids but also of inflammatory or coagulatory factors and oxidative stress, the precise molecular mechanisms underlying the long-term effects of LDL apheresis on the improvement of the peripheral circulation remains unclear and warrants further investigation.

DOI： 10.1111/j.1744-9987.2012.01149.x

PubMed

researchmap

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

Accumulated evidence suggests that an altered ambulatory blood pressure (BP) profile, particularly elevated nighttime BP, reflects target organ injury and is a better predictor of further cardiorenal risk than the clinic BP or daytime BP in hypertensive patients complicated by chronic kidney disease (CKD). In this study, we examined the beneficial effects of olmesartan, an angiotensin II type 1 receptor blocker (ARB), on ambulatory BP profiles and renal function in hypertensive CKD patients. Forty-six patients were randomly assigned to the olmesartan add-on group (n=23) or the non-ARB group (n=23). At baseline and after the 16-week treatment period, ambulatory BP monitoring was performed and renal function parameter measurements were collected. Although the baseline clinic BP levels and the after-treatment/baseline (A/B) ratios of clinic BP levels were similar in the olmesartan add-on and non-ARB groups, the A/B ratios of ambulatory 24-h and nighttime BP levels in the olmesartan add-on group were significantly lower. Furthermore, the A/B ratios of urinary protein, albumin and type IV collagen excretion in the olmesartan add-on group were significantly lower than those in the non-ARB group (urinary protein excretion, 0.72±0.41 vs. 1.45±1.48, P=0.030; urinary albumin excretion, 0.73±0.37 vs. 1.50±1.37, P=0.005; urinary type IV collagen excretion, 0.87±0.42 vs. 1.48±0.87, P=0.014) despite comparable A/B ratios for the estimated glomerular filtration rate in the two groups. These results indicate that in hypertensive patients with CKD, olmesartan add-on therapy improves the ambulatory BP profile via a preferential reduction in nighttime BP with concomitant renal injury inhibition.

DOI： 10.1038/hr.2012.184

PubMed

researchmap

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

DOI： 10.1038/hr.2012.166

PubMed

researchmap

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

The Ang II type 1 receptor (AT1R)-associated protein (ATRAP/Agtrap) is a molecule specifically interacting with the carboxyl- terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R. Accumulating evidence indicates that a tissue-specific regulatory balancing of ATRAP and AT1R expression may be involved in the modulation of AT1R signaling at local tissue sites and also in the pathophysiology of hypertension and its associated end-organ injury. Furthermore, the activation of ATRAP in transgenic-models inhibited inflammatory vascular remodeling and cardiac hypertrophy in response to Ang II stimulation. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and related organ injury.

PubMed

researchmap

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

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

PubMed

researchmap

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

The case of a 68-year-old woman with purpura nephritis associated with nephrotic syndrome is herein described. The patient's clinical course and the findings of a renal biopsy study revealed purpura nephritis. Following treatment with corticosteroids and intravenous cyclophosphamide accompanied by an angiotensin II type I receptor-blocker, an anti-platelet drug and an hydroxymethylglutaryl (HMG)-CoA, the proteinuria mildly decreased. Additional rituximab therapy led to a complete remission. This report describes our successful experience using rituximab to treat refractory nephrotic syndrome of purpura nephritis. Further studies are required to confirm the efficacy of rituximab as an alternative therapy for nephrotic syndrome.

PubMed

researchmap

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

Aliskiren is a direct renin inhibitor that exerts its effect at the rate-limiting step of the renin-angiotensin system. This study was performed to examine the beneficial effects of aliskiren-based antihypertensive therapy on the ambulatory blood pressure (BP) profile, central hemodybamics, and arterial stiffness in untreated Japanese patients with mild to moderate hypertension. Twenty-one Japanese nondiabetic patients with untreated mild to moderate essential hypertension were initially given aliskiren once daily at 150 mg, and the dose was titrated up to 300 mg as needed. After 12 weeks of aliskiren-based therapy, the clinic, ambulatory, and central BP values as well as brachial-ankle pulse wave velocity (baPWV) were all significantly decreased compared with baseline (clinic systolic BP, 151 ± 11 mm Hg vs 132 ± 11 mm Hg; clinic diastolic BP, 91 ± 13 mm Hg vs 82 ± 9 mm Hg; 24-hour systolic BP, 144 ± 12 mm Hg vs 133 ± 11 mm Hg; 24-hour diastolic BP, 88 ± 8 mm Hg vs 81 ± 9 mm Hg; central BP, 162 ± 16 mm Hg vs 148 ± 14 mm Hg; baPWV, 1625 ± 245 cm/s vs 1495 ± 199 cm/s; P<.05). These results show that aliskiren, as a first-line regimen, improves the ambulatory BP profile and may have protective vascular effects in Japanese nondiabetic patients with untreated mild to moderate essential hypertension.

DOI： 10.1111/j.1751-7176.2012.00640.x

PubMed

researchmap

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

We herein report the first case of remarkable hypertriglyceridemia induced by aliskiren. A 42-year-old man with chronic kidney disease who had been taking antihypertensive medication for approximately 10 years was treated with aliskiren at a dose of 150 mg/day due to uncontrolled hypertension. Six weeks later, although the patient's blood pressure decreased, a laboratory examination revealed remarkable hypertriglyceridemia and an elevated creatinine level. We suspected the occurrence of an adverse event of aliskiren, and the medication was discontinued. Thereafter, the hypertriglyceridemia and elevated creatinine level spontaneously improved. Transient eosinophilia and a strong-positive response of drug lymphocyte stimulation test (DLST) to aliskiren occurred during the patient's clinical course, and we determined the remarkable hypertriglyceridemia to be an adverse event of aliskiren.

PubMed

researchmap

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

Recent guidelines recommend combination antihypertensive therapy to achieve the target blood pressure (BP) and to suppress target organ damage. This study aimed to examine the beneficial effects of combination therapy with candesartan and amlodipine on BP control and markers of target organ function in Japanese essential hypertensive patients (N = 20) who did not achieve the target BP level during the monotherapy period with either candesartan or amlodipine. After the monotherapy period, for patients already being treated with amlodipine, a once-daily 8 mg dose of candesartan was added on during the combination therapy period (angiotensin II receptor blocker [ARB] add-on group, N = 10), and a once-daily 5 mg dose of amlodipine was added on for those already being treated with candesartan (calcium channel blocker [CCB] add-on group, N = 10). Combination therapy with candesartan and amlodipine for 12 weeks significantly decreased clinic and home systolic blood pressure (SBP) and diastolic blood pressure (DBP). In addition, the combination therapy was able to significantly reduce urine albumin excretion without decrease in estimated glomerular filtration ratio and resulted in significant improvements in brachial-ankle pulse wave velocity, central SBP, and insulin sensitivity. Furthermore, the CCB add-on group showed a significantly greater decrease in clinic and home DBP than the ARB add-on group. The calcium channel blocker add-on group also exhibited better improvements in vascular functional parameters than the ARB add-on group. These results suggest that combination therapy with candesartan and amlodipine is an efficient therapeutic strategy for hypertension with pleiotropic benefits.

DOI： 10.3109/10641963.2012.681081

PubMed

researchmap

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

Strict blood pressure (BP) control is reportedly important for the management of hypertensive patients with chronic kidney disease (CKD). The purpose of this cross-sectional study was to examine whether the variables of ambulatory BP and the heart rate (HR) profile, central hemodynamics, and arterial stiffness were closely related to the renal function parameters (urine albumin excretion rate [UACR] and estimated glomerular filtration rate [eGFR]) observed in 25 consecutive hospitalized hypertensive patients with CKD. There were significant positive relationships between UACR and 24-hour, daytime, and nighttime ambulatory systolic BP. In addition, there were significant negative relationships between UACR and 24-hour and daytime HR variability. The circulating B-type natriuretic peptide level and hemoglobin A1c were also positively related to UACR. With respect to eGFR, although the 24-hour and nighttime HR variability were positively associated with eGFR, the circulating pentosidine and nighttime HR had a negative relationship with eGFR. On the other hand, central hemodynamics and arterial stiffness did not exhibit any significant association with renal function parameters. These results indicate that ambulatory BP and the HR profile are closely modulated by renal function deterioration. Further studies are needed to investigate the causal relationship between ambulatory BP and the HR profile and renal function parameters in hypertensive patients with CKD.

DOI： 10.3109/10641963.2012.681082

PubMed

researchmap

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

DOI： 10.1038/hr.2011.149

PubMed

researchmap

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

OBJECTIVE: We previously showed that the molecule interacting with Ang II type 1 receptor (AT1R), ATRAP, promotes AT1R internalization and attenuates AT1R-mediated pathological responses. In this study we examined whether the regulation of renal ATRAP expression is related to the development of salt-induced hypertension and renal injury as well as to the beneficial effects of AT1R blockade. METHODS AND RESULTS: Dahl Iwai salt-sensitive hypertensive and Dahl Iwai salt-resistant rats were divided into six groups for the administration of vehicle or olmesartan either continuously from 3 to 16 weeks, or transiently from weaning to puberty (3-10 weeks), and fed high salt diet from 6 to 16 weeks. In Dahl Iwai salt-sensitive rats, not only continuous, but also prepubertal olmesartan treatment improved hypertension at 15 weeks. Renal ATRAP expression was suppressed in vehicle-treated Dahl Iwai salt-sensitive rats, concomitant with up-regulation of renal oxidative stress, inflammation and fibrosis-related markers such as p22phox, TGF-β, fibronectin, monocyte chemotactic protein-1 and type 1 collagen. However, prepubertal as well as continuous olmesartan treatment recovered the suppressed renal ATRAP expression and inhibited the renal activation of p22phox, TGF-β, fibronectin, MCP-1 and type 1 collagen. In Dahl Iwai salt-resistant rats, such suppression of renal ATRAP expression or induction of renal pathological responses by salt loading was not observed. CONCLUSIONS: These results indicate that prepubertal transient blockade of AT1R signaling exerts a long-term therapeutic effect on salt-induced hypertension and renal injury in Dahl Iwai salt-sensitive rats, partly through a sustained enhancement of renal ATRAP expression, thereby suggesting ATRAP a novel molecular target in salt-induced hypertension and renal injury.

DOI： 10.1097/HJH.0b013e32834a5a46

PubMed

researchmap

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

We previously cloned a molecule that interacts with angiotensin II type 1 (AT1) receptor to exert an inhibitory function on AT1 receptor signaling that we named ATRAP/Agtrap (for AT1 receptor-associated protein). In the present study we examined the regulation of basal ATRAP gene expression using renal distal convoluted tubule cells. We found that serum starvation upregulated basal expression of ATRAP gene, a response that required de novo mRNA and protein synthesis. Luciferase assay revealed that the proximal promoter region directs transcription and that a putative binding site of runt-related transcription factors (RBE) is important for transcriptional activation. The results of RBE-decoy transfection and endogenous knockdown by small interference RNA showed that the runt-related transcription factor Runx3 is involved in ATRAP gene expression. Chromatin immunoprecipitation assay also supported the binding of Runx3 to the ATRAP promoter in renal distal convoluted tubule cells. Immunohistochemistry demonstrated the expression of Runx3 and ATRAP proteins in the distal convoluted and connecting tubules of the kidney in consecutive sections. Furthermore, the Runx3 immunostaining was decreased together with a concomitant suppression of ATRAP expression in the affected kidney after 7 days of unilateral ureteral obstruction. These findings indicate that Runx3 plays a role in ATRAP gene expression in renal distal tubular cells both in vitro and in vivo.

DOI： 10.1152/physiolgenomics.00005.2011

PubMed

researchmap

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

Presently hypertensive patients with chronic kidney disease (CKD) particularly diabetic nephropathy are increasing in number, and cardiovascular and renal complications are the most common cause of death in these patients. The control of blood pressure (BP) is an important issue in cardiovascular and renal protection in hypertensive patients with CKD. Although hypertension is usually diagnosed based on measurements of BP recorded during a visit to a physician, that is, office BP, several studies have shown that target organ damage and prognosis are more closely associated with ambulatory BP than with office BP. It should be important to achieve the target absolute BP levels in hypertensive patients obtained either by office or home measurements or by ambulatory recordings for the cardiovascular and renal protection. Noninvasive techniques for measuring ambulatory BP have allowed BP to be monitored during both day and night. Additionally, ambulatory BP monitoring can provide information on circadian BP variation and short-term BP variability, which is suggested to be associated with cardiovascular and renal morbidity and mortality. This review will briefly summarize the emerging concept of anti-hypertensive therapy based on ambulatory BP profile in hypertensive patients with CKD.

PubMed

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：日本臨床分子医学会  

researchmap

Language：Japanese   Publisher：日本臨床分子医学会  

researchmap

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

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：(一社)日本アフェレシス学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：神奈川腎炎研究会  

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

J-GLOBAL

researchmap

Language：Japanese   Publisher：横浜市立大学医学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

J-GLOBAL

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

J-GLOBAL

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(株)先端医学社  

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(一社)和漢医薬学会  

researchmap

Language：Japanese   Publisher：(一社)和漢医薬学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(株)じほう  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

J-GLOBAL

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(株)先端医学社  

researchmap

Language：Japanese   Publisher：(株)先端医学社  

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese  

J-GLOBAL

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(一社)日本アフェレシス学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(株)日本臨床社  

researchmap

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

researchmap

Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

researchmap

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

researchmap

Web of Science

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：日本心脈管作動物質学会  

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

researchmap

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

researchmap

Language：Japanese   Publisher：(株)メジカルビュー社  

researchmap

Language：English  

DOI： 10.1097/01.hjh.0000420727.45381.dc

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(株)先端医学社  

researchmap

Language：Japanese   Publisher：日本心脈管作動物質学会  

researchmap

Language：Japanese   Publisher：(株)日本臨床社  

researchmap

Language：Japanese   Publisher：(株)ライフメディコム  

researchmap

Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

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

researchmap

Language：Japanese   Publisher：(株)東京医学社  

researchmap

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

researchmap

researchmap

researchmap

researchmap

researchmap