Large, prospective, clinical trials have confirmed the efficacy of intensive
blood-glucose control to prevent the onset and progression of
diabetic complications. However, since it is difficult to maintain
blood glucose concentrations close to the normal range, the effect of intensive
therapy to prevent
diabetic complications may be limited. Other approaches are therefore required to prevent the progression of
diabetic complications based on the elucidation of the
biological mechanisms. In this review, the impacts of mitochondrial
reactive oxygen species (ROS) on
diabetes-related complications are described. In endothelial cells, high
glucose levels increase mitochondrial ROS, and the normalization of mitochondrial ROS production by inhibitors of mitochondrial metabolism, or by the overexpression of UCP-1 or MnSOD, prevents the
glucose-induced accumulation of
sorbitol, activation of
protein kinase C, and formation of
advanced glycation end products, all of which are believed to be major molecular mechanisms of
diabetic complications. We also demonstrated that
8-hydroxydeoxyguanosine, which represents mitochondrial oxidative damage, was elevated in patients with either retinopathy,
albuminuria, or the increased intima-media thickness of carotid arteries compared to patients without
diabetic vascular complications. In addition, to investigate the impact of mitochondrial ROS on
diabetic retinopathy in vivo, we established a novel transgenic mouse, which specifically expressed MnSOD in endothelial cells. By the introduction of diabetes, levels of urinary
8-hydroxydeoxyguanosine and expressions of
VEGF and
fibronectin mRNA in retinas were increased in wild type littermates; however, these observations were ameliorated in transgenic mice. Taking the results together,
hyperglycemia could induce mitochondrial ROS production, associating it with the pathogenesis of
diabetic vascular complications.