Acceleration of diabetic renal injury in the superoxide dismutase knockout mouse: effects of tempol.
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.
DeRubertis
Frederick R
FR
Department of Medicine, VA Pittsburgh Healthcare System and University of Pittsburgh, School of Medicine, Pittsburgh, PA 15240, USA. frederick.derubertis@med.va.gov
Craven
Patricia A
PA
Melhem
Mona F
MF
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D006442:Glycated Hemoglobin / Q000032:analysis; D007444:Inulin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology; D013113:Spin Labels; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D013997:Time Factors
D000975:Antioxidants; D003497:Cyclic N-Oxides; D006442:Glycated Hemoglobin; D007444:Inulin; D009569:Nitric Oxide; D013113:Spin Labels; D013311:Streptozocin; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000606291:Sod1 protein, mouse; C001803:tempol