Podocyte as the target for aldosterone: roles of oxidative stress and Sgk1.
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.
Shibata
Shigeru
S
Department of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Nagase
Miki
M
Yoshida
Shigetaka
S
Kawachi
Hiroshi
H
Fujita
Toshiro
T
D000450:Aldosterone / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D000077545:Eplerenone; D006830:Hydralazine / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism* / Q000502:physiology; D007260:Infusion Pumps; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D019255:NADPH Oxidases / Q000378:metabolism; D009392:Nephrectomy / Q000379:methods; D018384:Oxidative Stress; D050199:Podocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology; D011507:Proteinuria / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D013113:Spin Labels; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
D000450:Aldosterone; D000959:Antihypertensive Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D000077545:Eplerenone; D006830:Hydralazine; D017874:Immediate-Early Proteins; D000451:Mineralocorticoid Receptor Antagonists; D019255:NADPH Oxidases; D017346:Protein Serine-Threonine Kinases; D018161:Receptors, Mineralocorticoid; D013113:Spin Labels; D013148:Spironolactone; D000099184:Serum-Glucocorticoid Regulated Kinases; C001803:tempol