Podocyte as the Target for Aldosterone: Roles of Oxidative Stress and Sgk1
Reads0
Chats0
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
More filters
Journal ArticleDOI
Aldosterone: effects on the kidney and cardiovascular system
Marie Briet,Ernesto L. Schiffrin +1 more
TL;DR: Several lines of evidence support the existence of crosstalk between aldosterone and angiotensin II in vascular smooth muscle cells, and large interventional trials that test the efficacy and safety of mineralocorticoid-receptor antagonists in chronic kidney disease are needed.
Journal ArticleDOI
Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis
TL;DR: Studying in mice in which the mineralocorticoid receptor has been deleted from specific cell types suggest a key role for macrophages in promoting inflammation and fibrosis, and studies in rodents genetically deficient in aldosterone synthase or treated with a pharmacological ald testosterone-synthase inhibitor are providing insight into the relative contribution.
Journal ArticleDOI
The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology
Say Viengchareun,Damien Le Menuet,Laetitia Martinerie,Mathilde Munier,Laurent Pascual-Le Tallec,Marc Lombès +5 more
TL;DR: The structure, molecular mechanism of action and transcriptional regulation mediated by MR are described, emphasizing the most recent developments at the cellular and molecular level.
Journal ArticleDOI
Aldosterone and end-organ damage.
Annis Marney,Nancy J. Brown +1 more
TL;DR: Whereas adrenalectomy improves glucose homoeostasis in hyperaldosteronism, MR antagonism may worsen glucose homOEostasis and impairs endothelial function in diabetes, suggesting a possible detrimental effect of aldosterone via non-genomic pathways.
Journal ArticleDOI
Aldosterone and Vascular Inflammation
TL;DR: This article reviews the current literature regarding mechanism(s) of aldosterone-induced vascular inflammation and its implications for the prevention of vascular injury in humans.
References
More filters
Journal ArticleDOI
Recommendations for Blood Pressure Measurement in Humans and Experimental Animals Part 1: Blood Pressure Measurement in Humans: A Statement for Professionals From the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research
Thomas G. Pickering,John E. Hall,Lawrence J. Appel,Bonita Falkner,John W. Graves,Martha N. Hill,Daniel W. Jones,Theodore W. Kurtz,Sheldon G. Sheps,Edward J. Roccella +9 more
TL;DR: It is increasingly recognized that office measurements correlate poorly with blood pressure measured in other settings, and that they can be supplemented by self-measured readings taken with validated devices at home, which gives a better prediction of risk than office measurements and is useful for diagnosing white-coat hypertension.
Journal ArticleDOI
NAD(P)H Oxidase: Role in Cardiovascular Biology and Disease
TL;DR: Vascular NAD(P)H oxidases have been found to be essential in the physiological response of vascular cells, including growth, migration, and modification of the extracellular matrix and have been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.
Journal ArticleDOI
Positionally Cloned Gene for a Novel Glomerular Protein—Nephrin—Is Mutated in Congenital Nephrotic Syndrome
Marjo Kestilä,Ulla Lenkkeri,Minna Männikkö,Jane Lamerdin,Paula McCready,Heli Putaala,Vesa Ruotsalainen,Takako Morita,Marja Nissinen,Riitta Herva,Clifford E. Kashtan,Leena Peltonen,Christer Holmberg,Anne S. Olsen,Karl Tryggvason,Karl Tryggvason +15 more
TL;DR: A crucial role for this protein in the development or function of the kidney filtration barrier is demonstrated and by Northern and in situ hybridization was shown to be specifically expressed in renal glomeruli.
Journal ArticleDOI
Cell Biology of the Glomerular Podocyte
TL;DR: This review integrates recent physiological and molecular understanding of the role of podocytes during the maintenance and failure of the glomerular filtration barrier with hereditary nephrotic syndromes identified over the last 2 years.
Journal ArticleDOI
Pathophysiology of Progressive Nephropathies
Giuseppe Remuzzi,Tullio Bertani +1 more
TL;DR: In patients with renal diseases characterized by proteinuria, the initial insult to the kidney is usually followed by a progressive decline in the glomerular filtration rate, which is thought to be due to changes in renal hemodynamics initiated by the loss of nephrons.