Renal and metabolic effects of tempol in obese ZSF1 rats--distinct role for superoxide and hydrogen peroxide in diabetic renal injury.
Oxidative stress, that is, overproduction of reactive oxygen species and reduced antioxidant system activity, is implicated in the pathogenesis of diabetic complications; and therefore, superoxide dismutase (SOD) mimetic tempol should be protective in diabetic kidney. However, the effects of tempol in metabolic syndrome-associated renal injury have not been thoroughly examined. In this study, we examined the effects of 9 weeks of treatment with tempol on metabolic status, renal oxidative stress, and kidney function and structure in obese, diabetic, hypertensive ZSF(1) rats and their nondiabetic, hypertensive, lean littermates. The obese rats had significantly reduced total SOD and catalase activity, increased peroxidase activity and lipid peroxidation, and higher level of protein oxidation in renal cortical tissue compared with their lean littermates. These changes were accompanied by renal injury (proteinuria; reduced excretory function; and markedly increased glomerular and interstitial inflammation, proliferation, and collagen IV synthesis). Tempol treatment slightly increased total SOD activity, significantly reduced lipid peroxidation and peroxidase activity, but had no effect on catalase and protein oxidation. Tempol had no effects on blood pressure, renal hemodynamics and excretory function, and proteinuria in obese rats, yet improved insulin sensitivity and reduced renal inflammatory, proliferative, and fibrotic changes. Because tempol possesses no catalase activity and, in diabetes, not only SOD but also catalase is inhibited, it is possible that the toxicity of hydrogen peroxide (H(2)O(2)) remains unaltered under tempol treatment. This study suggests that superoxide and H(2)O(2) may have distinct roles in the pathogenesis of diabetic renal injury, with superoxide mainly being involved in inflammatory, proliferative, and fibrotic changes, and H(2)O(2) in glomerular hemodynamics and proteinuria.
Rafikova
Olga
O
Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Salah
Eman M
EM
Tofovic
Stevan P
SP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007674:Kidney Diseases / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
D000975:Antioxidants; D001786:Blood Glucose; D003497:Cyclic N-Oxides; D007328:Insulin; D020738:Leptin; D013113:Spin Labels; D013481:Superoxides; D006861:Hydrogen Peroxide; D002374:Catalase; D009195:Peroxidase; D013482:Superoxide Dismutase; C001803:tempol