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

Metabolism. 2007 Sep;56(9):1256-64. doi: 10.1016/j.metabol.2007.04.024.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Cyclic N-Oxides / pharmacology*
  • Cyclic N-Oxides / therapeutic use*
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / genetics
  • Diabetic Nephropathies / pathology*
  • Disease Progression
  • Glycated Hemoglobin A / analysis
  • Inulin / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide / physiology
  • Spin Labels
  • Streptozocin
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase-1
  • Time Factors

Substances

  • Antioxidants
  • Cyclic N-Oxides
  • Glycated Hemoglobin A
  • Spin Labels
  • Nitric Oxide
  • Streptozocin
  • Inulin
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • tempol