Mitochondrial reactive oxygen species in the pathogenesis of early diabetic nephropathy.

Abstract

Over the past 40 years, a number of seemingly unrelated mechanisms have been implicated in the early stages of glucose-mediated damage responsible for diabetic complications. Starting in 2000, a series of publications showed that each of these mechanisms reflects a single hyperglycemia-induced process: overproduction of superoxide by the mitochondrial electron transport chain. This discovery created a paradigm shift in the field1,2. In the kidney, hyperglycemia causes increased reactive oxygen species (ROS) in both glomerular mesangial cells and proximal tubular cells. The central pathogenic role of hyperglycemia-induced superoxide in initating diabetic glomerular injury is directly supported by the observation that overexpression of superoxide dismutase as a transgene protects 8-month-old diabetic mice from developing increased fractional mesangial volume, increased glomerular transforming growth factor-β, increased collagen IV and increased plasma creatinine3. Transgenic expression of superoxide dismutase (SOD) similarly prevents diabetic retinopathy and cardiomyopathy. This paradigm has been challenged in a recent paper by Dugan et al.4, who claim that in the diabetic kidney, ROS are decreased rather than increased. The authors also report that adenine monophosphate (AMP)-activated protein kinase (AMPK) activity, proliferator-activated receptor γ coactivator 1α (PGC1α) protein level and mitochondrial density are decreased in the diabetic kidney, and suggest that these reflect a feed-forward cycle of decreased AMPK activity, decreased PGC1α, and decreased mitochondrial biogenesis, initiated and maintained by decreased mitochondrial ROS production.