Renal Tubule Angiotensin II Type 1 Receptor–Associated Protein Promotes Natriuresis and Inhibits Salt‐Sensitive Blood Pressure Elevation

Wakui, Hiromichi; Uneda, Kazushi; Tamura, Kouichi; Ohsawa, Masato; Azushima, Kengo; Kobayashi, Ryu; Ohki, Kohji; Dejima, Toru; Kanaoka, Tomohiko; Tsurumi‐Ikeya, Yuko; Matsuda, Miyuki; Haruhara, Kotaro; Nishiyama, Akira; Yabana, Machiko; Fujikawa, Tetsuya; Yamashita, Akio; Umemura, Satoshi

doi:10.1161/jaha.114.001594

Cited by 18 publications

(23 citation statements)

References 52 publications

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“…It is noteworthy that adipocyte‐specific ATRAP enhancement did not result in any evident alteration in physiological function, including adipose tissue morphology, when mice were fed an LFD. This finding is consistent with our previous studies demonstrating that the change in ATRAP expression did not affect physiological function or organ morphology at baseline in other types of ATRAP transgenic and deficient mice . In contrast, adipocyte‐specific AT1R deficiency promoted striking adipocyte hypertrophy under baseline conditions on LFD feeding and failed to improve HFD‐induced visceral obesity and insulin resistance .…”

Section: Discussionsupporting

confidence: 92%

“…This finding is consistent with our previous studies demonstrating that the change in ATRAP expression did not affect physiological function or organ morphology at baseline in other types of ATRAP transgenic and deficient mice. 11,[13][14][15]19,21 In contrast, adipocyte-specific AT1R deficiency promoted striking adipocyte hypertrophy under baseline conditions on LFD feeding and failed to improve HFDinduced visceral obesity and insulin resistance. 22 Consistent with this, severe hypotension and abnormal renal morphology and function at baseline were caused by a systemic deficiency of renin, angiotensinogen, and AT1R, respectively.…”

Section: Discussionmentioning

confidence: 98%

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Adipocyte‐Specific Enhancement of Angiotensin II Type 1 Receptor‐Associated Protein Ameliorates Diet‐Induced Visceral Obesity and Insulin Resistance

Azushima

Ohki

Wakui

et al. 2017

JAHA

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 98%

Adipocyte‐Specific Enhancement of Angiotensin II Type 1 Receptor‐Associated Protein Ameliorates Diet‐Induced Visceral Obesity and Insulin Resistance

Azushima

Ohki

Wakui

et al. 2017

JAHA

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“…However, ATRAP exerts no evident influence on the physiological AT1R signaling pathway. For example, the phenotype of ATRAP transgenic mice with overexpression of ATRAP in cardiovascular tissue is similar to that of their littermate WT control mice under nonstimulating conditions . In the current study, there were no significant differences in blood pressure, cardiovascular injury, and glucose/fat metabolism profiles between aged ATRAP‐KO and WT mice (Figure ; Table).…”

Section: Discussionsupporting

confidence: 52%

“…For example, the phenotype of ATRAP transgenic mice with overexpression of ATRAP in cardiovascular tissue is similar to that of their littermate WT control mice under nonstimulating conditions. 19,20,23,38,40,41 In the current study, there were no ATRAP, angiotensin II type 1 receptor-associated protein; Bnip3, B-cell lymphoma 2/ adenovirus E1B 19-kDa interacting protein 3; KO mice, angiotensin II type 1 receptorassociated protein-knockout mice; PGC-1a, peroxisome proliferator-activated receptor c coactivator-1a; UCP2, uncoupling protein 2; WT mice, wild-type mice. significant differences in blood pressure, cardiovascular injury, and glucose/fat metabolism profiles between aged ATRAP-KO and WT mice (Figure 2; Table).…”

Section: Discussionmentioning

confidence: 56%

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Angiotensin II Type 1 Receptor‐Associated Protein Regulates Kidney Aging and Lifespan Independent of Angiotensin

Uneda

Wakui

Maeda

et al. 2017

JAHA

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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.

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Tissue xanthine oxidoreductase activity in a mouse model of aristolochic acid nephropathy

et al. 2021

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Xanthine oxidoreductase (XOR) is a critical enzyme in purine metabolism and uric acid production, and its levels are reported to increase during stress, thereby promoting organ damage. Herein, we investigated the activity of XOR in a mouse model of aristolochic acid I (AA)-induced nephropathy, a type of nephrotoxic chronic kidney disease (CKD). A persistent decrease in renal function was observed in mice up to 4 weeks after 4 weeks of AA (2.5 mg kg À1) administration. Renal histology revealed an increase in tubular interstitial fibrosis over time. Although AA administration did not change XOR activity in the plasma, heart, liver, or muscle, XOR activity was persistently increased in renal tissue. Our results suggest that the renal tissue-specific increase in XOR activity is involved in the progression of tubulo-interstitial disorders, specifically fibrosis.

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Renal Tubule Angiotensin II Type 1 Receptor–Associated Protein Promotes Natriuresis and Inhibits Salt‐Sensitive Blood Pressure Elevation

Cited by 18 publications

References 52 publications

Adipocyte‐Specific Enhancement of Angiotensin II Type 1 Receptor‐Associated Protein Ameliorates Diet‐Induced Visceral Obesity and Insulin Resistance

Adipocyte‐Specific Enhancement of Angiotensin II Type 1 Receptor‐Associated Protein Ameliorates Diet‐Induced Visceral Obesity and Insulin Resistance

Angiotensin II Type 1 Receptor‐Associated Protein Regulates Kidney Aging and Lifespan Independent of Angiotensin

Tissue xanthine oxidoreductase activity in a mouse model of aristolochic acid nephropathy

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