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Inhibition of NADPH oxidase prevents AGE mediated damage in diabetic nephropathy through a protein kinase C- dependent pathway.

¹ JDRF Albert Einstein Centre for Diabetes Complications, Diabetes and Metabolism Division, Baker Medical Research Institute, Melbourne, Victoria, AUSTRALIA.
²Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina USA
³Department of Medicine and Immunology, Monash University, AMREP Precinct, Melbourne, Victoria, Australia

Objective: Excessive production of reactive oxygen species (ROS) via NADPH oxidase has been implicated in the pathogenesis of diabetic nephropathy. Since NADPH oxidase activation is closely linked to other putative pathways, its interaction with changes in PKC and increased advanced glycation was examined.

Research Design and Methods: Streptozotocin diabetic or non-diabetic Sprague Dawley rats were followed for 32 wks with groups randomised to no treatment or the NADPH oxidase assembly inhibitor apocynin (15 mg/kg/day: wk 16-32). Complementary in vitro studies were performed in which primary rat mesangial cells, in the presence and absence of AGE-BSA, were treated with either apocynin or the PKC- inhibitor Ro-32-0432.

Results: Apocynin attenuated diabetes-associated increases in albuminuria and glomerulosclerosis. Circulating, renal cytosolic and skin collagen-associated AGE levels in diabetic rats were not reduced by apocynin. Diabetes-induced translocation of PKC, specifically PKC- to renal membranes, was associated with increased NADPH dependent superoxide production and elevated renal, serum and urinary VEGF concentrations. In both diabetic rodents and in AGE-treated mesangial cells, blockade of NADPH oxidase or PKC- attenuated cytosolic superoxide, PKC activation and increased VEGF. Finally renal extracellular matrix accumulation of fibronectin and collagen IV was decreased by apocynin.

Conclusions: In the context of these and previous findings by our group we conclude that activation of NADPH oxidase via phosphorylation of PKC- is downstream of the AGE-RAGE interaction in diabetic renal disease and may provide a novel therapeutic target for diabetic nephropathy.

Key Words: Protein Kinase C- • Advanced Glycation End-products • Receptor of Advanced Glycation End Products • Apocynin • Kidney • NADPH oxidase • Reactive Oxygen Species • Carboxymethyllysine

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				S.-i. Yamagishi Comment on: Thallas-Bonke et al. (2008) Inhibition of NADPH Oxidase Prevents Advanced Glycation End Product-Mediated Damage in Diabetic Nephropathy Through a Protein Kinase C-{alpha}-Dependent Pathway: Diabetes 57:460-469, 2008 Diabetes, June 1, 2008; 57(6): e13 - e13. [Full Text] [PDF]

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