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Oxidative Stress as a Major Culprit in Kidney Disease in Diabetes

¹ Juvenile Diabetes Research Foundation Albert Einstein Centre for Diabetes Complications, Division of Diabetes and Metabolism, Baker Heart Research Institute, Melbourne, Australia
² Departments of Medicine and Immunology, Monash University, AMREP, Melbourne, Australia

Corresponding author: Professor Mark Cooper, Head, JDRF Albert Einstein Centre, Division of Diabetes and Metabolism, Baker Heart Research Institute, P.O. Box 6492, St. Kilda Rd. Central, Melbourne, Vic 8008, Australia. E-mail: mark.cooper{at}baker.edu.au

Abbreviations: AGE, advanced glycation end product; FFA, free fatty acid; G6PDH, glucose-6-phosphate dehydrogenase; NOS, nitric oxide synthase; RAGE, receptor for AGEs; RAS, renin-angiotensin system, ROS, reactive oxygen species; SOD, superoxide dismutase

It is postulated that localized tissue oxidative stress is a key component in the development of diabetic nephropathy. There remains controversy, however, as to whether this is an early link between hyperglycemia and renal disease or develops as a consequence of other primary pathogenic mechanisms. In the kidney, a number of pathways that generate reactive oxygen species (ROS) such as glycolysis, specific defects in the polyol pathway, uncoupling of nitric oxide synthase, xanthine oxidase, NAD(P)H oxidase, and advanced glycation have been identified as potentially major contributors to the pathogenesis of diabetic kidney disease. In addition, a unifying hypothesis has been proposed whereby mitochondrial production of ROS in response to chronic hyperglycemia may be the key initiator for each of these pathogenic pathways. This postulate emphasizes the importance of mitochondrial dysfunction in the progression and development of diabetes complications including nephropathy. A mystery remains, however, as to why antioxidants per se have demonstrated minimal renoprotection in humans despite positive preclinical research findings. It is likely that the utility of current study approaches, such as vitamin use, may not be the ideal antioxidant strategy in human diabetic nephropathy. There is now an increasing body of data to suggest that strategies involving a more targeted antioxidant approach, using agents that penetrate specific cellular compartments, may be the elusive additive therapy required to further optimize renoprotection in diabetes.

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