Accumulating evidence suggests that
mineralocorticoid receptor blockade effectively reduces
proteinuria in hypertensive patients. However, the mechanism of the antiproteinuric effect remains elusive. In this study, we investigated the effects of
aldosterone on podocyte, a key player of the glomerular filtration barrier. Uninephrectomized rats were continuously infused with
aldosterone and fed a high-
salt diet.
Aldosterone induced
proteinuria progressively, associated with blood pressure elevation. Notably, gene expressions of podocyte-associated molecules
nephrin and
podocin were markedly decreased in
aldosterone-infused rats at 2 weeks, with a gradual decrease thereafter. Immunohistochemical studies and electron microscopy confirmed the podocyte damage. Podocyte injury was accompanied by renal reduced
nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of
aldosterone effector
kinase Sgk1. Treatment with
eplerenone, a selective
aldosterone receptor blocker, almost completely prevented podocyte damage and
proteinuria, with normalization of elevated reduced
nicotinamide-adenine dinucleotide phosphate oxidase activity. In addition,
proteinuria, podocyte damage, and Sgk1 upregulation were significantly alleviated by
tempol, a membrane-permeable
superoxide dismutase, suggesting the pathogenic role of oxidative stress. Although
hydralazine treatment almost normalized blood pressure, it failed to improve
proteinuria and podocyte damage. In cultured podocytes with consistent expression of
mineralocorticoid receptor,
aldosterone stimulated membrane translocation of reduced
nicotinamide-adenine dinucleotide phosphate oxidase cytosolic components and oxidative stress generation in podocytes. Furthermore,
aldosterone enhanced the expression of Sgk1, which was inhibited by
mineralocorticoid receptor antagonist and
tempol. In conclusion, podocytes are injured at the early stage in
aldosterone-infused rats, resulting in the occurrence of
proteinuria.
Aldosterone can directly modulate podocyte function, possibly through the induction of oxidative stress and Sgk1.