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

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 m 2 , 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. Electronic supplementary material The online version of this article (10.1186/s12933-019-0912-3) contains supplementary material, which is available to authorized users.

Introduction: Obesity-related glomerulopathy (ORG) is a slowly progressive kidney disease occurring in association with obesity. It is characterized histopathologically by glomerulomegaly, likely caused by single-nephron hyperfiltration that has not been demonstrated in humans because of technical difficulty in measuring single-nephron glomerular filtration rate (SNGFR) in the clinical setting. Methods: Total glomerular number per kidney, with or without global glomerulosclerosis, was estimated by the combination of cortical volume assessment via unenhanced computed tomography and biopsybased stereology. Mean glomerular volume was calculated from the measured area of glomerular tufts. Both SNGFR and single-nephron urinary protein excretion (SNUPE) were estimated by dividing values for estimated glomerular filtration rate and urinary protein excretion by the number of nonsclerotic glomeruli. Living kidney donors were used as healthy controls. Results: A total of 48 ORG patients with average nonsclerotic glomerular numbers of 456,000 AE 235,000 per kidney were included. The values for SNGFR in ORG patients with chronic kidney disease (CKD) stages 1 and 2 were higher than for nonobese and obese controls (97 AE 43 vs. 59 AE 21 vs. 64 AE 21 nl/min, respectively, P ¼ 0.001). Nonsclerotic glomerular number decreased with advancing stages of renal functional impairment. The presence of ORG with more advanced CKD stages was associated with lower SNGFR and marked elevation in SNUPE levels, with no difference in the mean glomerular volume between the stages. Conclusions: These results provide functional evidence for single-nephron hyperfiltration in patients with ORG, and identify compensatory failure to maintain effective SNGFR as a feature of advanced-stage ORG.

A low GD together with marked glomerular enlargement characterizes renal biopsy samples of children born with a LBW at an early stage of gestation.

BackgroundThe 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 ResultsWe 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.ConclusionsThese 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.

IntroductionObesity-related glomerulopathy is an established secondary glomerular disease that may occur in obese individuals with a body mass index (BMI) of ≥30 kg/m2. However, patients with moderate obesity (BMI ≤ 30 kg/m2) may also develop this disease.MethodsA total of 20 patients with grade 1 obesity (25 ≤ BMI < 30 kg/m2) with persistent proteinuria, without evidence of other renal diseases, were analyzed retrospectively. These patients were compared with 20 patients with grade 2 or higher obesity (BMI ≥ 30 kg/m2) with persistent proteinuria. Biopsies of 31 kidney transplant donors as healthy controls were used to compare histologic parameters.ResultsSimilar to the grade 2 or higher obesity group, the grade 1 obesity group had a male predominance (85%) and showed a high incidence of hypertension (80%). Urinary protein excretion and renal outcome parameters were comparable between the groups. Patients with grade 1 obesity showed typical histologic features of obesity-related glomerulopathy: low glomerular density with glomerulomegaly. The glomerular density and mean glomerular volume in the grade 1 group, the grade 2 or higher group, and the kidney transplant donors with grade 1 obesity were 1.6 ± 0.8 versus 1.4 ± 0.6 versus 3.0 ± 1.1 (per mm2) and 6.1 ± 2.1 versus 6.4 ± 1.6 versus 2.9 ± 0.8 (×106 μm3), respectively.DiscussionA glomerulopathy similar to obesity-related glomerulopathy can occur in moderately obese individuals. Renal factor(s), such as low glomerular density, may thus underlie susceptibility to this disease entity as well as BMI.

BackgroundAngiotensin 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 ResultsRenal 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.ConclusionsThese 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.