title: Podocyte COX-2 exacerbates diabetic nephropathy by increasing podocyte (pro)renin receptor expression.
abstract: 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.
authors: George M. O’Brien Kidney and Urologic Diseases Center and Division of Nephrology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Huifang
authors: H
authors: Cheng
authors: Xiaofeng
authors: X
authors: Fan
authors: Gilbert W
authors: GW
authors: Moeckel
authors: Raymond C
authors: RC
authors: Harris
mesh_terms: D000818:Animals; D002478:Cells, Cultured / Q000187:drug effects; D003470:Culture Media / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000517:prevention & control; D005947:Glucose / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013449:Sulfonamides / Q000627:therapeutic use; D000093342:Prorenin Receptor; D000096926:Benzenesulfonamides
chemical_list: D003470:Culture Media; D051546:Cyclooxygenase 2; D016861:Cyclooxygenase Inhibitors; D005947:Glucose; D011720:Pyrazoles; D011956:Receptors, Cell Surface; D013449:Sulfonamides; D000093342:Prorenin Receptor; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C077623:Ptgs2 protein, mouse