Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease

Shibata, Shigeru; Nagase, Miki; Yoshida, Shigetaka; Kawarazaki, Wakako; Kurihara, Hidetake; Tanaka, Hirotoshi; Miyoshi, Jun; Takai, Yoshimi; Fujita, Toshiro

doi:10.1038/nm.1879

Cited by 406 publications

(406 citation statements)

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“…Administration of an anti-CF6 antibody at 113 μg/kg for three consecutive days to transgenic mice improved the salt-induced hypertension. Since RAC1, a member of the Rho family GTPases, was recently identified as a determinant molecule for salt-sensitive hypertension via activation of mineralocorticoid receptor [22], we measured RAC1 activity in the kidney of transgenic mice. Pull-down assays revealed that transgenic mice had more active GTPases than control wild-type mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A high-salt diet increased systolic and diastolic blood pressure in transgenic mice, and this salt-induced hypertension was improved by administration of an anti-CF6 antibody. Since RAC1 was recently identified as a determinant molecule for salt-sensitive hypertension via activation of mineralocorticoid receptor [22], we investigated a possible involvement of RAC1 activation in the genesis of salt-sensitive hypertension in transgenic mice. Pull-down assays clearly showed that transgenic mice had more active GTPases in the kidney than wild-type mice, while RAC1-GTP was increased by extracellular acidosis and amiloride administration.…”

Section: Discussionmentioning

confidence: 99%

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Coupling factor 6-induced activation of ecto-F1Fo complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice

Osanai

Tanaka

Magota³

et al. 2011

Diabetologia

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Aims/hypothesis Despite advances in pharmacological treatments, diabetes with hypertension continues to be a major public health problem with high morbidity and mortality rates. We recently identified a circulating peptide coupling factor 6 (CF6), which binds to the plasma membrane ATP synthase (ecto-F 1 F o complex), resulting in intracellular acidosis. We investigated whether overexpression of CF6 contributes to diabetes and hypertension by intracellular acidosis. Methods Transgenic mice overexpressing CF6 (also known as ATP5J) were generated, and physiological, biochemical and molecular biology studies were performed. Results CF6 overexpression elicited a sustained decrease in intracellular pH in tissues (aorta, kidney, skeletal muscle and liver, with the exception of adipose tissue) that express its receptor, the β-subunit of ecto-F 1 F o complex. Consistent with the receptor distribution, phospho-insulin receptor β, phosphoinositide 3-kinase activity and the phospho-Akt1: total Akt1 ratio were all decreased in the skeletal muscle and the liver in transgenic compared with wild-type mice, resulting in a decrease of plasma membrane-bound GLUT4 and an increase in hepatic glucose production. Under a high-sucrose diet, transgenic mice had insulin resistance and mild glucose intolerance; under a high-salt diet, they had elevated blood pressure with increased renal RASrelated C3 botulinum substrate 1 (RAC1)-GTP, which is an activator of mineralocorticoid receptor. Conclusions/interpretation Through its action on the β-subunit of ecto-F 1 F o complex, which results in intracellular acidosis, CF6 plays a crucial role in the development of insulin resistance and hypertension. This finding might advance our understanding of the mechanisms underlying diabetes and hypertension, possibly also providing a novel therapeutic target against cardiovascular disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Coupling factor 6-induced activation of ecto-F1Fo complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice

Osanai

Tanaka

Magota³

et al. 2011

Diabetologia

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“…It has been reported that MRs were activated by Rac1, which was independent of aldosterone in the kidney. 43 Further studies are needed to clarify the precise mechanisms involved in the activation of MR in the RVLM.…”

Section: Discussionmentioning

confidence: 99%

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

et al. 2012

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Mineralocorticoid receptor (MR) is recognized as a target for therapeutic intervention in hypertension and heart failure. MRs in the central nervous system are thought to have an important role in blood pressure regulation. Thus, we examined whether activation of the MR pathway in the rostral ventrolateral medulla (RVLM) of the brainstem contributes to the neural mechanism of hypertension in stroke-prone spontaneously hypertensive rats (SHRSPs). We microinjected eplerenone, aldosterone or Na + -rich artificial cerebrospinal fluid (aCSF) into the RVLM of anesthetized Wistar-Kyoto (WKY) rats and SHRSPs. Arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. The expressions of the MR protein and the serumand glucocorticoid-regulated kinase protein (Sgk1), which is a marker of MR activity, in the RVLM were measured by western blot analysis. Bilateral microinjection of eplerenone into the RVLM decreased AP and RSNA in WKY rats and SHRSPs, and the decreases in those variables were significantly greater in SHRSPs than WKY rats. Microinjection of aldosterone or Na + -rich aCSF into the RVLM increased AP and RSNA dose-dependently. The increases in those variables were significantly greater in SHRSPs than in WKY rats. The pressor responses of aldosterone or Na + -rich aCSF were attenuated by the prior injection of eplerenone in SHRSPs. Sgk1 expression levels in the RVLM were significantly greater in SHRSPs than in WKY rats. These findings suggest that activation of MRs in the RVLM enhances sympathetic activity, thereby contributing to the neural mechanism of hypertension in the SHRSP.

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“…They have identified a new role for Rac1, a member of the Rho family of GTPases, as a potent activator of MR signal transduction both in vitro and in vivo. 26 The constitutively active Rac1 enhances nuclear translocation and the transcriptional activity of MR in vitro. They showed that a unique Rac-specific inhibitor, NSC23766, effectively ameliorates proteinuria and glomerular damage in the DS rats.…”

Section: Effects Of Eplerenone In Experimental Animal Models With Salmentioning

confidence: 99%

Effects of eplerenone, a selective mineralocorticoid receptor antagonist, on clinical and experimental salt-sensitive hypertension

Takeda

2009

Hypertens Res

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Mineralocorticoid receptors (MRs) are expressed in non-epithelial tissues, such as blood vessels, the heart and adipose tissue. The combined effects of aldosterone and insulin link the metabolic syndrome with hypertension and salt sensitivity. Eplerenone is the newly developed inhibitor of MRs that has significantly fewer adverse effects than similar doses of spironolactone. Eplerenone has been reported to have anti-hypertensive and protective effects on cardiovascular and renal injury in salt-sensitive hypertensive animal models, such as the Dahl salt-sensitive (DS) hypertensive rat and leptin receptor-deficient spontaneously hypertensive rat (SHR/cp). Eplerenone also increases nitric oxide bioavailability and improves impaired endothelial function by decreasing oxidative stress. Clinical studies support the concept that eplerenone is effective for the treatment of salt-sensitive hypertension as well as idiopathic hyperaldosteronism and does not have adverse anti-androgenic adverse effects. In Japan, eplerenone has been used clinically since 2007 for the treatment of hypertension, with its price being marginally lower than all types of angiotensin II receptor antagonists. This will inevitably result in an increasing number of hypertensive patients and those with primary aldosteronism being treated with this agent in the near future. Experimental studies have shown that the profibrotic actions of aldosterone develop only in association with a high-sodium diet. Excess sodium intake is a major contributing factor in the pathogenesis of hypertension, and large population-based studies have shown that there is a significant correlation between the level of salt intake and blood pressure and the frequency of hypertension. In this report, we review the clinical and experimental evidence for the use of the selective receptor antagonist, eplerenone, in the treatment of saltsensitive hypertension. This review also examines how this evidence has contributed to our understanding of the pathophysiological mechanisms of salt-sensitive hypertension.

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Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease

Cited by 406 publications

References 34 publications

Coupling factor 6-induced activation of ecto-F1Fo complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice

Coupling factor 6-induced activation of ecto-F1Fo complex induces insulin resistance, mild glucose intolerance and elevated blood pressure in mice

Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats

Effects of eplerenone, a selective mineralocorticoid receptor antagonist, on clinical and experimental salt-sensitive hypertension

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