Role of mitochondria and mitochondorial DNA damage due to oxidative stress in progressive renal disease *
Reactive oxygen species (ROS) have been demonstrated to play a crucial role in the pathophysiology of various renal diseases. We studied the possible implication of mitochondrial injury induced by oxidative stress in progressive forms of renal diseases. We examined mitochondrial oxidative damage and deterioration of mitochondrial function in a 5/6 nephrectomiz-ed remnant kidney model (Nx) , and found generation of significant amount of ROS in the Nx glomeruli. Urinary excretion of 8-hydroxy-deoxyguanosine (8-OHdG) , which is a product and biomarker of oxidative DNA damage, significantly increased 20 weeks after nephrectomy. Immunohistochemical studies using a monoclonal antibody against 8-OHdG revealed accumula-tions of 8-OHdG mainly in the cytosol of glomerular epithelial and endothelial cells. We examined the expression of the NADH dehydrogenase 2 and cytochrome b genes, which encode proteins consisting of complex I and HI , respectively, and found that they were suppressed in the Nx 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 IE , respectively, increased ROS production. The direct influence of ROS on the mitochondria was also examined. On exposure to hydrogen peroxide, the GECs showed a loss of mitochondrial membrane potential (^X^m). Chromatin condensation and nuclear fragmentation, which are features of apoptotic cell death, were demonstrated in the GECs. These results indicated that oxidative injuries to the mitochondria and mtDNA play an important role in the development of progressive renal diseases.(Accepted on October 14, 2003)
