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.
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Involvement of oxidative stress in the profibrotic action of aldosterone: Interaction with the renin-angiotensin system
TL;DR: The data suggest that the profibrotic but not the hypertrophic action of aldosterone are mediated at least in part by reactive oxygen species generation and involve an interaction with the renin-angiotensin system.
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Podocyte damage is a critical step in the development of glomerulosclerosis in the uninephrectomised-desoxycorticosterone hypertensive rat.
TL;DR: The crucial damage to the glomerulus in this model would appear to be attributable to podocyte failure, with the resultant GBM denudation triggering synechia formation, hyalinosis and ultimately glomerulosclerosis.
Journal ArticleDOI
Aldosterone Stimulates Collagen Gene Expression and Synthesis Via Activation of ERK1/2 in Rat Renal Fibroblasts
Yukiko Nagai,Kayoko Miyata,Guang Ping Sun,Matlubur Rahman,Shoji Kimura,Akira Miyatake,Hideyasu Kiyomoto,Masakazu Kohno,Youichi Abe,Masanori Yoshizumi,Akira Nishiyama +10 more
TL;DR: It is suggested that aldosterone stimulates collagen gene expression and synthesis via MR-mediated ERK1/2 activation in renal fibroblasts, which may contribute to the progression of ald testosterone-induced tubulointerstitial fibrosis.
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Increased expression of mineralocorticoid effector mechanisms in kidney biopsies of patients with heavy proteinuria.
Marcus Quinkler,Daniel Zehnder,Kevin S. Eardley,Julia Lepenies,Alexander J. Howie,Susan V. Hughes,Paul Cockwell,Martin Hewison,Paul M. Stewart +8 more
TL;DR: These studies support animal data linking aldosterone/MR activation to renal inflammation and proteinuria and further studies are urgently required to assess the potential beneficial effects of MR antagonism in patients with renal disease.
Journal ArticleDOI
Different Contributions of Endothelin-A and Endothelin-B Receptors in the Pathogenesis of Deoxycorticosterone Acetate–Salt–Induced Hypertension in Rats
Yasuo Matsumura,Norio Hashimoto,Shima Taira,Toshihiko Kuro,Rika Kitano,Mamoru Ohkita,Terry J. Opgenorth,Masanori Takaoka +7 more
TL;DR: Results strongly support the view that ETA receptor-mediated action plays an important role in the pathogenesis of DOCA-salt-induced hypertension and seem likely that the ETB receptor- mediated action protects against vascular and renal injuries in this model of hypertension.