Aberrant Rac1-mineralocorticoid receptor pathways in salt-sensitive hypertension

被引:16
作者
Kawarazaki, Wakako [1 ]
Fujita, Toshiro [1 ]
机构
[1] Univ Tokyo 1, Div Clin Epigenet, Res Ctr Adv Sci & Technol 1, Tokyo 1538904, Japan
基金
日本科学技术振兴机构; 日本学术振兴会;
关键词
aldosterone; aldosterone-releasing factors; kidney; metabolic syndrome; mineralocorticoid receptor; obesity; Rac1; salt sensitivity of blood pressure; salt-sensitive hypertension; ACTIVATED PROTEIN-KINASE; JUN NH2-TERMINAL KINASE; MINERALOCORTICOID RECEPTOR; ANGIOTENSIN-II; BLOOD-PRESSURE; INTRACEREBROVENTRICULAR INFUSION; METABOLIC SYNDROME; OXIDATIVE STRESS; RAC1; GTPASE; WEIGHT-LOSS;
D O I
10.1111/1440-1681.12177
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:929 / 936
页数:8
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