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

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.

• Authors: Wakako Kawarazaki, Toshiro Fujita
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 40 Issue 12 Pg. 929-36 (Dec 2013) ISSN: 1440-1681 [Electronic] Australia
• PMID: 24111570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2013 Wiley Publishing Asia Pty Ltd.

Chemical References

• RAC1 protein, human
• Receptors, Mineralocorticoid
• Sodium Chloride, Dietary
• Aldosterone
• Sodium
• rac1 GTP-Binding Protein

Topics

• Aldosterone (blood, metabolism)
• Animals
• Humans
• Hypertension (blood, etiology, metabolism)
• Kidney (metabolism)
• Metabolic Syndrome (blood, etiology, metabolism)
• Rats
• Receptors, Mineralocorticoid (metabolism)
• Renin-Angiotensin System (physiology)
• Signal Transduction
• Sodium (metabolism)
• Sodium Chloride, Dietary (adverse effects)
• Sympathetic Nervous System (metabolism)
• rac1 GTP-Binding Protein (metabolism)