Podocyte as the Target for Aldosterone: Roles of Oxidative Stress and Sgk1
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TLDR
In this article, the effects of aldosterone on podocyte, a key player of the glomerular filtration barrier, were investigated in uninephrectomized rats and fed a high-salt diet, where the podocyte injury was accompanied by renal reduced nicotinamide-adenine dinucleotide phosphate oxidase activation, increased oxidative stress, and enhanced expression of Sgk1.Abstract:
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.read more
Citations
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Oxidant Mechanisms in Renal Injury and Disease
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Effects of tempol and redox-cycling nitroxides in models of oxidative stress
TL;DR: Tempol is a redox-cycling nitroxide that promotes the metabolism of many reactive oxygen species (ROS) and improves nitric oxide bioavailability and has been studied extensively in animal models of oxidative stress.
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Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease
Shigeru Shibata,Miki Nagase,Shigetaka Yoshida,Wakako Kawarazaki,Hidetake Kurihara,Hirotoshi Tanaka,Jun Miyoshi,Yoshimi Takai,Toshiro Fujita +8 more
TL;DR: Evidence is provided that signaling cross-talk between Rac1 and mineralocorticoid receptor modulates mineralocortex receptor activity and Rac1 is identified as a therapeutic target for chronic kidney disease.
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Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides
TL;DR: 4-Hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) is the most extensively studied nitroxide and broadly effective in reducing blood pressure, whether given by acute intravenous injection or by prolonged administration, in a wide range of rodent models of hypertension.
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Podocyte injury and its consequences.
TL;DR: The cellular aspects of podocyte dysfunction and the adaptive or maladaptive glomerular responses to podocyte injury that lead to its major consequence, glomerulosclerosis are focused on.
References
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Journal ArticleDOI
SGK1 as a determinant of kidney function and salt intake in response to mineralocorticoid excess.
Volker Vallon,Dan Yang Huang,Florian Grahammer,Amanda W. Wyatt,Hartmut Osswald,Peer Wulff,Dietmar Kuhl,Florian Lang +7 more
TL;DR: DOCA/1% NaCl treatment enhanced renal Na(+) excretion significantly more in sgk1(+/+) mice (from 3 +/- 1 to 134 +/- 32 micromol.g body wt(-1)), pointing to SGK1-dependent stimulation of salt intake, kidney growth, proteinuria, and renal K(+)excretion during mineralocorticoid excess.
Journal ArticleDOI
Dietary Salt Regulates Renal SGK1 Abundance Relevance to Salt Sensitivity in the Dahl Rat
TL;DR: Evidence is provided that the abundance of serum and glucocorticoid-induced kinase 1 in rat kidney may play a role in salt adaptation and the pathogenesis of hypertension and suggests that aldosterone is not the primary inducer of SGK1 in the Sprague-Dawley rat.
Journal ArticleDOI
Sgk1 Gene Expression in Kidney and Its Regulation by Aldosterone: Spatio-Temporal Heterogeneity and Quantitative Analysis
TL;DR: The serine-threonine kinase sgk1 was recently identified as a gene rapidly induced by mineralocorticoids, resulting in increased sodium transport in vitro, and in situ hybridization was performed on kidneys of mice having aldosterone excess over a range of doses and durations.
Journal ArticleDOI
Up-Regulation of the Human Serum and Glucocorticoid-Dependent Kinase 1 in Glomerulonephritis
Bjoern Friedrich,S. Wärntges,Karin Klingel,Martina Sauter,Reinhard Kandolf,Teut Risler,Gerhard A. Müller,Ralph Witzgall,Wilhelm Kriz,Hermann Josef Gröne,Florian Lang +10 more
TL;DR: In conclusion, glomerulonephritis leads to glomerular and in some cases to epithelial up-regulation of hSGK1 transcription, a serine/threonine kinase participating in the regulation of Na+ transport.
Journal ArticleDOI
The Many Targets of Aldosterone
TL;DR: The authors conclude that sodium channels are induced by genomic effects of aldosterone, which result in sodium influx and cell depolarization, creating an electrochemical gradient that leads to chloride and water accumulation and cell swelling.