Podocyte COX-2 exacerbates diabetic nephropathy by increasing podocyte (pro)renin receptor expression.

Cheng H, Fan X, Moeckel GW, Harris RC
J Am Soc Nephrol. 2011 22 (7): 1240-51

PMID: 21737546 · PMCID: PMC3137572 · DOI:10.1681/ASN.2010111149

Diabetic nephropathy (DN) increases podocyte cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition reduces proteinuria and glomerular injury in animal models of diabetes. To investigate the role of podocyte COX-2 in development of diabetic nephropathy, we employed a streptozotocin model of diabetic mellitus in wild-type and transgenic mice expressing COX-2 selectively in podocytes. Progressive albuminuria developed only in diabetic COX-2 transgenic mice despite hyperglycemia, BP, and GFR being similar to those in wild-type mice. Transgenic mice also manifested significant foot-process effacement, moderate mesangial expansion, and segmental thickening of the glomerular basement membrane. In cultured podocytes overexpressing COX-2, high glucose induced cell injury and increased both expression of the pro(renin) receptor and activation of the renin-angiotensin system. Downregulation of the (pro)renin receptor attenuated the injury induced by high glucose. In vivo, podocyte pro(renin) receptor expression increased in diabetic COX-2-transgenic mice, and treatment with a COX-2 inhibitor abrogated the upregulation of (pro)renin receptor and reduced albuminuria, foot-process effacement, and mesangial matrix expansion. In summary, these results demonstrate that increased expression of podocyte COX-2 predisposes to diabetic glomerular injury and that the (pro)renin receptor may be one mediator for this increased susceptibility to injury.

Copyright © 2011 by the American Society of Nephrology

MeSH Terms (15)

Animals Cells, Cultured Culture Media Cyclooxygenase 2 Cyclooxygenase Inhibitors Diabetes Mellitus, Experimental Diabetic Nephropathies Glucose Male Mice Mice, Transgenic Podocytes Pyrazoles Receptors, Cell Surface Sulfonamides

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