Mineralocorticoid receptors, salt-sensitive hypertension, and metabolic syndrome.
Obese persons with metabolic syndrome often have associated with salt-sensitive hypertension, microalbuminuria, and cardiac dysfunction, and the plasma aldosterone level in one-third of metabolic syndrome patients is clearly elevated. Hyperaldosteronism, which may be caused at least partially by certain adipocyte-derived factors, contributes to the development of proteinuria in obese hypertensive rats, and salt loading aggravates the proteinuria and induces cardiac diastolic dysfunction because of inadequate suppression of plasma aldosterone level. However, mineralocorticoid receptor (MR) antagonists prevent salt-induced renal and cardiac damage, suggesting that aldosterone excess and a high-salt diet exert an unfavorable synergistic action on the kidney and heart. In Dahl salt-sensitive rats, however, despite appropriate suppression of plasma aldosterone with a high-salt diet, salt loading paradoxically activated renal MR signaling, and the renal injury was markedly prevented by MR antagonists. Accordingly, we discovered an alternative pathway of MR activation in which Rac1, a small GTP-binding protein, activates MRs. Salt loading activates renal Rac1 in Dahl salt-sensitive rats, and Rac1 in turn induces MR activation, which results in renal injury, and the renal injury has been found to be prevented by Rac1 inhibitors. Moreover, several metabolic syndrome-related factors induce Rac1 activation, and one of them, hyperglycemia, activates MRs via Rac1 activation. Consistent with this, Rac1 inhibitors attenuated the proteinuria and renal injury in obese hypertensive animals. Thus, both salt and obesity activate Rac1 and cause MR activation. Abnormal activation of the aldosterone/MR pathway plays a key role in the development of salt-sensitive hypertension and renal injury in metabolic syndrome.
Fujita
Toshiro
T
Department of Nephrology and Endocrinology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. fujita-dis@h.u-tokyo.ac.jp
D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000150:complications / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000378:metabolism
D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D000450:Aldosterone