Role of mitochondrial and mitochondrial DNA damage due to oxidative stress in diabetic nephropathy *
Augmented oxidative stress induced by hyperglycemia possibly contributes to the pathogenesis of diabetic complications. We studied mitochondrial injury induced by hyperglycemia and its relevance to the development of diabetic nephropathy (DN) using a streptozotocin (STZ) -induced diabetic model. We examined mitochondrial oxidative damage and mitochondrial function relative to reactive oxygen species (ROS). ROS were generated in diabetic glomeruli. Urinary excretion of 8-hydroxy-deoxyguanosine (8-OH-dG), which is a product and biomarker of oxidative DNA damage, significantly increased after induction of hyperglycemia by STZ. Immunohistochemical studies using the monoclonal antibody against 8-OH-dG revealed accumulations of 8-OH-dG mainly the cytosol of glomerular epithelial and endothelial cells. We examined the expression of the NADH dehydrogenase 2 and cytochrome b genes, which encode structural proteins consisting of complexes I and III, respectively. The expression of these genes was inhibited in STZ rats. We examined the effects of mitochondrial respiratory chain inhibitors on ROS production in rat glomerular epithelial cells (GECs). Rotenone and antimycin A, which inhibit complexes I and III, respectively, increased ROS production. The direct influence of ROS on the mitochondria was examined. Following the addition of hydrogen peroxide, the GECs showed loss of mitochondrial membrane potential (△Ψm). Chromatin condensation and nuclear fragmentation of GECs were demonstrated following the addition of hydrogen peroxide. These results indicated that oxidative injuries to the mitochondria and mtDNA play an important role in the development of DN through oxidative modification of mtDNA. (Accepted on October 27, 2000) Kawasaki Igakkaishi 27(1) : 67-82, 2001
