Aldosterone-and-Salt-Induced Cardiac Fibrosis Is Independent from Angiotensin II Type 1a Receptor Signaling in Mice

Kagiyama, Shuntaro; Matsumura, Kiyoshi; Fukuhara, Mikio; Sakagami, Kanae; Fujii, Koji; Iida, Mitsuo

doi:10.1291/hypres.30.979

Cited by 19 publications

(17 citation statements)

References 30 publications

(26 reference statements)

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“…Moreover, aldosterone and salt synergically promoted organ damage in the heart and kidney. 25 The present study demonstrated that irbesartan prevented renal and cardiac organ damage even in a condition of “aldosterone breakthrough.” These findings suggest possible new clinical benefits of using irbesartan to treat such fibrotic conditions in patients treated with ARBs.…”

Section: Discussionsupporting

confidence: 53%

Cardiac and Renal Protective Effects of Irbesartan via Peroxisome Proliferator‐Activated Receptorγ–Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1a Receptor Blockade in Mouse Model of Salt‐Sensitive Hypertension

Kusunoki

Taniyama

Rakugi

et al. 2013

JAHA

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Background“Aldosterone breakthrough” observed in patients receiving long‐term treatment with angiotensin blockade is strongly associated with increased risk of left ventricular hypertrophy, poor exercise capacity, refractory proteinuria, and declining glomerular filtration rate through the profibrotic actions of aldosterone. To overcome aldosterone breakthrough, we examined the additional organ‐protective actions of irbesartan, because irbesartan is an angiotensin II type 1 receptor (AT1R) blocker (ARB) with peroxisome proliferator‐activated receptor (PPAR)γ agonistic effects, which mediate organ‐protective effects independent of AT1R blockade. In this study, we examined the organ‐protective effects of irbesartan in a salt‐sensitive hypertension model using AT1aR knockout mice.Methods and ResultsAldosterone and 1% NaCl treatment resulted in a significant increase in severe cardiac and renal fibrosis. Irbesartan, but not losartan, significantly reduced renal fibrosis, glomerular injury through inhibition of macrophage infiltration, epithelial–mesenchymal transition, and oxidative stress. Similarly, cardiac fibrosis and myocyte hypertrophy were decreased by irbesartan, but not losartan, treatment, associated with a significant reduction in oxidative stress. Importantly, anti–hepatocyte growth factor (HGF) neutralizing antibody and a PPARγ antagonist (GW9662) attenuated these organ‐protective effects of irbesartan. HGF protein level was increased by irbesartan, especially in the kidney and heart, while GW9662 treatment inhibited the increase in HGF level.ConclusionsIn this study, we showed that irbesartan, which has not only AT1aR‐blocking effects, but also PPARγ agonistic effects accompanied by HGF expression, inhibited organ damage by aldosterone and salt treatment. Second‐generation ARBs such as irbesartan, which has the dual actions of AT1R blockade and PPARγ activation, may have clinical value for the treatment of hypertensive patients with aldosterone breakthrough.

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Section: Discussionsupporting

confidence: 53%

Cardiac and Renal Protective Effects of Irbesartan via Peroxisome Proliferator‐Activated Receptorγ–Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1a Receptor Blockade in Mouse Model of Salt‐Sensitive Hypertension

Kusunoki

Taniyama

Rakugi

et al. 2013

JAHA

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“…showed as well that aldosterone caused greater BP elevation and cardiac hypertrophy in another strain of Agtr1a −/− compared to WT, and cardiac fibrosis only in Agtr1a −/− mice. 40 The mechanism of excess BP increase in aldosterone-infused Agtr1a −/− mice could be related to compensatory effects of MR signaling pathways in presence of the Agtr1a gene deletion, or to a kidney defect in sodium and water excretion.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors

et al. 2016

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We investigated the role of angiotensin type 1a receptors (AGTR1a) in vascular injury induced by aldosterone activation of mineralocorticoid receptors (MR) in Agtr1a−/− and wild-type mice infused with aldosterone for 14 days while receiving 1% NaCl in drinking water. Aldosterone increased systolic blood pressure by ~30 mmHg in wild-type mice, and ~50 mmHg in Agtr1a−/− mice. Aldosterone induced aortic and small artery remodeling and impaired endothelium-dependent relaxation in wild-type mice, and enhanced fibronectin and collagen deposition, and vascular inflammation. None of these vascular effects were observed in Agtr1a−/− mice. Aldosterone effects were prevented by the AGTR1 antagonist losartan in wild-type mice. In contrast to aldosterone, norepinephrine caused similar BP increase and mesenteric artery remodeling in wild-type and Agtr1a−/− mice. Agtr1a−/− mice infused with aldosterone did not increase sodium excretion in response to a sodium chloride challenge, suggesting sodium retention that could contribute to the exaggerated blood pressure rise induced by aldosterone. Agtr1a−/− mice had decreased mesenteric artery expression of the calcium-activated potassium channel Kcnmb1, which may enhance myogenic tone and together with sodium retention exacerbate BP responses to aldosterone/salt in Agtr1a−/− mice. We conclude that although aldosterone activation of MR raises BP more in Agtr1a−/− mice, AGTR1a is required for MR stimulation to induce vascular remodeling and inflammation, and endothelial dysfunction.

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“…In several of the experiments, vehicle or olmesartan (10 mg·kg Ϫ1 ·day Ϫ1 ) in the drinking water was administrated for the same period. The ANG II and olmesartan dosages were determined from previous reports (10,18,48). Following experimental treatment, the mice were anesthetized and the tissues were removed into liquid nitrogen or fixative.…”

Section: Methodsmentioning

confidence: 99%

Intrarenal suppression of angiotensin II type 1 receptor binding molecule in angiotensin II-infused mice

Wakui

Tamura²,

Matsuda³

et al. 2010

American Journal of Physiology-Renal Physiology

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ATRAP [ANG II type 1 receptor (AT1R)-associated protein] is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous ANG II infusion on the intrarenal expression and distribution of ATRAP and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1,000, or 2,500 ng·kg(-1)·min(-1) for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2,500 ng·kg(-1)·min(-1)) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and the α-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng·kg(-1)·min(-1)), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.

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Aldosterone-and-Salt-Induced Cardiac Fibrosis Is Independent from Angiotensin II Type 1a Receptor Signaling in Mice

Cited by 19 publications

References 30 publications

Cardiac and Renal Protective Effects of Irbesartan via Peroxisome Proliferator‐Activated Receptorγ–Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1a Receptor Blockade in Mouse Model of Salt‐Sensitive Hypertension

Cardiac and Renal Protective Effects of Irbesartan via Peroxisome Proliferator‐Activated Receptorγ–Hepatocyte Growth Factor Pathway Independent of Angiotensin II Type 1a Receptor Blockade in Mouse Model of Salt‐Sensitive Hypertension

Aldosterone-Induced Vascular Remodeling and Endothelial Dysfunction Require Functional Angiotensin Type 1a Receptors

Intrarenal suppression of angiotensin II type 1 receptor binding molecule in angiotensin II-infused mice

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