Deletion of the angiotensin II type 1 receptor–associated protein enhances renal sodium reabsorption and exacerbates angiotensin II–mediated hypertension

Ohsawa, Masato; Tamura, Kouichi; Wakui, Hiromichi; Maeda, Akinobu; Dejima, Toru; Kanaoka, Tomohiko; Azushima, Kengo; Uneda, Kazushi; Tsurumi‐Ikeya, Yuko; Kobayashi, Ryu; Matsuda, Miyuki; Uchida, Shinichi; Toya, Yoshiyuki; Kobori, Hiroyuki; Nishiyama, Akira; Yamashita, Akio; Ishikawa, Yoshihiro; Umemura, Satoshi

doi:10.1038/ki.2014.95

Cited by 52 publications

(48 citation statements)

References 66 publications

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“…Our work indicates that NO inhibition induces the overexpression of AT1R in the kidney, contributing to hypertension and renal damage. Ohsawa et al [31] have shown that renal AT1R activation promotes sodium retention via ENaC activation, and consecutively the exacerbation of hypertension induced by Ang II administration.…”

Section: Discussionmentioning

confidence: 99%

Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension

et al. 2015

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Aims Activation of the renin–angiotensin system (RAS), renal oxidative stress and inflammation are constantly present in experimental hypertension. Nitric oxide (NO) inhibition with Nw-nitro-L-arginine methyl ester (L-NAME) has previously been reported to produce hypertension, increased expression of Angiotensin II (Ang II) and renal dysfunction. The use of Losartan, an Ang II type 1 receptor (AT1R) antagonist has proven to be effective reducing hypertension and renal damage; however, the mechanism by which AT1R blockade reduced kidney injury and normalizes blood pressure in this experimental model is still complete unknown. The current study was designed to test the hypothesis that AT1R activation promotes renal NAD(P)H oxidase up-regulation, oxidative stress and cytokine production during L-NAME induced-hypertension. Main methods Male Sprague–Dawley rats were distributed in three groups: L-NAME, receiving 70 mg/100 ml of L-NAME, L-NAME + Los, receiving 70 mg/100 ml of L-NAME and 40 mg/kg/day of Losartan; and Controls, receiving water instead of L-NAME or L-NAME and Losartan. Key findings After two weeks, L-NAME induced high blood pressure, renal overexpression of AT1R, NAD(P)H oxidase sub-units gp91, p22 and p47, increased levels of oxidative stress, interleukin-6 (IL-6) and interleukin-17 (IL-17). Also, we found increased renal accumulation of lymphocytes and macrophages. Losartan treatment abolished the renal expression of gp91, p22, p47, oxidative stress and reduced NF-κB activation and IL-6 expression. Significance These findings indicate that NO induced-hypertension is associated with up-regulation of NADPH oxidase, oxidative stress production and overexpression of key inflammatory mediators. These events are associated with up-regulation of AT1R, as evidenced by their reversal with AT1R blocker treatment.

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Section: Discussionmentioning

confidence: 99%

Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension

et al. 2015

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“…ATRAP‐KO mice generated on a C57BL/6 background by targeted gene disruption were used in the study . All experiments were performed with age‐matched ATRAP‐KO mice and WT mice (3–4, 11–12, and 22–25 months old; n=6–11 in each group).…”

Section: Methodsmentioning

confidence: 99%

“…Histological analysis was performed as described previously . The heart, aorta, and kidney were fixed with 4% PFA and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted from renal tissues with ISOGEN (Nippon Gene Co, Ltd, Toyama, Japan), and cDNA was synthesized using the SuperScript III First‐Strand System (Invitrogen). Time quantitative reverse‐transcription polymerase chain reaction was performed with an ABI PRISM 7000 Sequence Detection System by incubating the reverse‐transcription product with TaqMan PCR Master Mix and designed TaqMan probes (collagen‐1α, Mm00801666_g1; collagen‐3α, Mm01254476_m1; transforming growth factor‐β, Mm01178820_m1; tumor necrosis factor‐α, Mm00443258_m1; uncoupling protein 2, Mm00627599_m1; peroxisome proliferator‐activated receptor γ coactivator‐1α [PGC‐1α], Mm01208835_m1; BCL2/adenovirus E1B 19‐kDa interacting protein 3, Mm01275600_g1; calcium‐modulating cyclophilin ligand [CAML], Mm00500327_m1; nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2 [NFATc2/NFAT1], Mm01240677_m1; nuclear factor of activated T cells, cytoplasmic, calcineurin‐dependent 4 [NFATc4/NFAT3], Mm00452375_m1; nuclear factor of activated T cells, cytoplasmic, calcineurin‐dependent 3 [NFATc3/NFAT4], Mm01249200_m1 and interleukin‐2, Mm00434256_m1; Applied Biosystems, Foster City, CA), as described previously . mRNA levels were normalized to those of the 18S rRNA control.…”

Section: Methodsmentioning

confidence: 99%

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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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“…ATRAP deficiency exacerbated angiotensin-II-mediated hypertension by pathological activation of renal tubular AT1R. This directly stimulates ENaC in the distal tubules and enhances sodium retention in an aldosterone-independent manner while NCC seems not to be implicated in this mechanism [66 ].…”

Section: Enac Regulation By Renin-angiotensinaldosterone System (Raas)mentioning

confidence: 98%

Regulation of blood pressure and renal function by NCC and ENaC: lessons from genetically engineered mice

Verouti¹,

Boscardin²,

Hummler³

et al. 2015

Current Opinion in Pharmacology

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Deletion of the angiotensin II type 1 receptor–associated protein enhances renal sodium reabsorption and exacerbates angiotensin II–mediated hypertension

Cited by 52 publications

References 66 publications

Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension

Role of Angiotensin II type 1 receptor on renal NAD(P)H oxidase, oxidative stress and inflammation in nitric oxide inhibition induced-hypertension

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

Regulation of blood pressure and renal function by NCC and ENaC: lessons from genetically engineered mice

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