Resveratrol Improves Oxidative Stress and Protects Against Diabetic Nephropathy Through Normalization of Mn-SOD Dysfunction in AMPK/SIRT1-Independent Pathway

Abstract

OBJECTIVE: Despite the beneficial effects of resveratrol (RSV) on cardiovascular disease and life span, its effects on type 2 diabetic nephropathy remain unknown. This study examined the renoprotective effects of RSV in db/db mice, a model of type 2 diabetes. RESEARCH DESIGN AND METHODS: db/db mice were treated with RSV (0.3% mixed in chow) for 8 weeks. We measured urinary albumin excretion (UAE), histological changes (including mesangial expansion, fibronectin accumulation, and macrophage infiltration), oxidative stress markers (urinary excretion and mitochondrial content of 8-hydroxy-2'-deoxyguanosine [8-OHdG], nitrotyrosine expression), and manganese-superoxide dismutase (Mn-SOD) activity together with its tyrosine-nitrated modification and mitochondrial biogenesis in the kidney. Blood glucose, glycated hemoglobin, and plasma lipid profiles were also measured. The phosphorylation of 5'-AMP-activated kinase (AMPK) and expression of silent information regulator 1 (SIRT1) in the kidney were assessed by immunoblotting. RESULTS: RSV significantly reduced UAE and attenuated renal pathological changes in db/db mice. Mitochondrial oxidative stress and biogenesis were enhanced in db/db mice; however, Mn-SOD activity was reduced through increased tyrosine-nitrated modification. RSV ameliorated such alterations and partially improved blood glucose, glycated hemoglobin, and abnormal lipid profile in db/db mice. Activation of AMPK was decreased in the kidney of db/db mice compared with db/m mice. RSV neither modified AMPK activation nor SIRT1 expression in the kidney. CONCLUSIONS: RSV ameliorates renal injury and enhanced mitochondrial biogenesis with Mn-SOD dysfunction in the kidney of db/db mice, through improvement of oxidative stress via normalization of Mn-SOD function and glucose-lipid metabolism. RSV has antioxidative activities via AMPK/SIRT1-independent pathway.