Aldosterone has emerged as a deleterious hormone in the kidney, for example as a potent inducer of proteinuria. We identified the podocyte, the final filtration barrier in the glomerulus, as a novel target of aldosterone. Activation of the mineralocorticoid receptor (MR) in the podocyte disrupts the filtration barrier and induces proteinuria. Recent clinical and experimental studies have shown the efficacy of MR antagonism in reducing albuminuria in patients or rodent models of type 1 and type 2 diabetes. We assessed the pathogenic role of aldosterone in SHR/NDmcr-cp, a rat model of type 2 diabetes/metabolic syndrome. Podocyte injury and proteinuria were early manifestations of nephropathy in this model, and were exacerbated by high-salt feeding. Inappropriate activation of the aldosterone/MR system, possibly via adipocytederived aldosterone releasing factors, underlay the renal damage. Furthermore, we identified Rac1, a Rho family small GTPase, as a novel ligand-independent activator of MR. This alternative pathway of MR activation, indeed, contributed to podocyte injury in proteinuric kidney disease. In conclusion, MR can be activated by several different pathways, both aldosterone- dependently and -independently, leading to podocyte impairment and progression of proteinuric kidney disease. MR antagonists are promising anti-proteinuric drugs in diabetes, although hyperkalemia is a concern.
Keywords: Aldosterone, Mineralocorticoid receptor activation, Albuminuria, Podocyte injury, Mineralocorticoid receptor antagonist, Aldosterone breakthrough, Mineralocorticoid Receptor System, ESRD, mineralocorticoid receptor (MR, reactive oxygen species, Randomized Aldactone Evaluation, ACE, ACEIs, ARBs, PROTEINURIA, serum- and glu-cocorticoid-inducible kinase 1 (Sgk1), macrophage chemoattractant protein-1, growth factor (TGF)-1, interleukin-6, SHR, deoxycorticosterone ace-tate (DOCA), chronic kidney disease (CKD), trandola-pril, GFR, Hyperka-lemia, amlodipine, spironolactone, eplerenone, glomerulosclerosis, activator inhibitor (PAI)-1, TGF-1, macrophage infiltration, CTGF, streptozotocin (STZ), CD2AP, podocin, actinin 4, NEPH1, TRPC6, phospholipase C (PLC)1, proteinuric renal diseases, nephrotic syndrome, lupus nephritis, hypertensive nephropathy, obesity-related glomerulopathy, RAAS, catecholamines, endothelins, natriuretic peptides, adrenomedullin, nitric oxide, lucigenin chemiluminescence, p67phox, Rac1, anti-oxidant, tempol
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