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Clin Exp Pharmacol Physiol. 2013 Dec;40(12):929-36. doi: 10.1111/1440-1681.12177.

Aberrant Rac1-mineralocorticoid receptor pathways in salt-sensitive hypertension.

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1
Division of Clinical Epigenetics, Research Center for Advanced Science and Technology=1, The University of Tokyo=1, Tokyo, Japan.

Abstract

According to Guyton's model, impaired renal sodium excretion plays a key role in the increased salt sensitivity of blood pressure (BP). Several factors contribute to impaired renal sodium excretion, including the sympathetic nervous system, the renin-angiotensin system and aldosterone. Accumulating evidence suggests that abnormalities in aldosterone and its receptor (i.e. the mineralocorticoid receptor (MR)) are involved in the development of salt-sensitive (SS) hypertension. Patients with metabolic syndrome often exhibit hyperaldosteronism and are susceptible to SS hypertension. Aldosterone secretion from the adrenal glands is not suppressed in obese hypertensive rats fed a high-salt diet because of the abundant production of adipocyte-derived aldosterone-releasing factors, which are independent of the negative feedback regulation of aldosterone secretion by the renin-angiotensin-aldosterone system. Increased plasma aldosterone levels lead to SS hypertension via MR activation in the kidney. Renal MR activity is increased in Dahl salt-sensitive rats fed a high-salt diet, despite the appropriate suppression of plasma aldosterone levels. In this rat strain, activation of MR in the distal nephron causes salt-induced hypertension. This paradoxical response of the MR to salt loading can be attributed to activation of Rac1, a small GTPase. In the presence of aldosterone, activated Rac1 synergistically and directly activates MR in a ligand-independent manner. Thus, Rac1 activation in the kidney determines the salt sensitivity of BP. Together, the available evidence suggests that the aberrant Rac1-MR pathway plays a key role in the development of SS hypertension.

KEYWORDS:

Rac1; aldosterone; aldosterone-releasing factors; kidney; metabolic syndrome; mineralocorticoid receptor; obesity; salt sensitivity of blood pressure; salt-sensitive hypertension

PMID:
24111570
DOI:
10.1111/1440-1681.12177
[Indexed for MEDLINE]
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