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Metabolism. 2007 Sep;56(9):1256-64.

Acceleration of diabetic renal injury in the superoxide dismutase knockout mouse: effects of tempol.

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  • 1Department of Medicine, VA Pittsburgh Healthcare System and University of Pittsburgh, School of Medicine, Pittsburgh, PA 15240, USA.


Indices of renal injury and oxidative stress were examined in mice with deficiency of cytosolic Cu(2+)/Zn(2+) superoxide dismutase (SOD1-/-, KO) and their wild-type (WT) littermates with streptozotocin-induced diabetes. After 5 weeks of diabetes, KO diabetic (D) but not WT-D mice developed marked albuminuria, increases in glomerular content of transforming growth factor beta, collagen alpha1(IV), and nitrotyrosine, and higher glomerular superoxide compared with corresponding values in nondiabetics. After 5 months of diabetes, increases in these parameters, mesangial matrix expansion, renal cortical malondialdehyde content, and severity of tubulointerstitial injury were all significantly greater, whereas cortical glutathione was lower, in KO-D than in WT-D. In contrast to WT-D, after 4 weeks of diabetes, KO-D mice did not develop the increase in inulin clearance (C(In)) characteristic of early diabetes. The nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methylester suppressed C(In) in WT-D, but had no effect on C(In) in KO-D. Treatment of KO-D with the SOD mimetic tempol for 4 weeks suppressed albuminuria, increases in glomerular transforming growth factor beta, collagen alpha1(IV), nitrotyrosine, and glomerular superoxide, and concurrently increased C(In). The latter action of tempol in KO-D was blocked by the N(omega)-nitro-l-arginine methylester. The findings provide support for a role for superoxide and its metabolism by SOD1 in the pathogenesis of renal injury in diabetes in vivo, and implicate increased interaction of superoxide with nitric oxide as a pathogenetic factor.

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