Inhibition of NADPH Oxidase Prevents Advanced Glycation End Product–Mediated Damage in Diabetic Nephropathy Through a Protein Kinase C-α–Dependent Pathway

摘要: OBJECTIVE —Excessive production of reactive oxygen species (ROS) via NADPH oxidase has been implicated in the pathogenesis diabetic nephropathy. Since activation is closely linked to other putative pathways, its interaction with changes protein kinase C (PKC) and increased advanced glycation was examined. RESEARCH DESIGN AND METHODS —Streptozotocin-induced or nondiabetic Sprague Dawley rats were followed for 32 weeks, groups randomized no treatment assembly inhibitor apocynin (15 mg · kg −1 day ; weeks 16–32). Complementary vitro studies performed which primary rat mesangial cells, presence absence end products (AGEs)-BSA, treated either PKC-α Ro-32-0432. RESULTS —Apocynin attenuated diabetes-associated increases albuminuria glomerulosclerosis. Circulating, renal cytosolic, skin collagen–associated AGE levels not reduced by apocynin. Diabetes-induced translocation PKC, specifically membranes, associated NADPH-dependent superoxide elevated renal, serum, urinary vascular endothelial growth factor (VEGF) concentrations. In both rodents AGE-treated blockade cytosolic PKC VEGF. Finally, extracellular matrix accumulation fibronectin collagen IV decreased CONCLUSIONS —In context these previous findings our group, we conclude that phosphorylation downstream AGE–receptor disease may provide a novel therapeutic target