Oxidative stress has been known to play an important role in the development and progression of diabetic nephropathy, but
the intracellular signal transduction pathways regulated by reactive oxygen species (ROS) have not been clearly defined. High
glucose (HG) induces intracellular ROS directly via glucose metabolism and auto-oxidation and indirectly through the formation
of advanced glycation end products and their receptor binding. ROS mimic the stimulatory effects of HG and upregulate transforming
growth factor-â1, plasminogen activator inhibitor-1, and extracellular matrix (ECM) proteins by glomerular mesangial cells,
thus leading to mesangial expansion. ROS activate other signaling molecules, such as protein kinase C and mitogenactivated
protein kinases and transcription factors, such as nuclear factor-êB, activator protein-1, and specificity protein 1 leading
to transcription of genes encoding cytokines, growth factors, and ECM proteins. Finally, various antioxidants inhibit mesangial
cell activation by HG and ameliorate features of diabetic nephropathy.
These findings qualify ROS as intracellular messengers and as integral glucose-signaling molecules in glomerular mesangial
cells in diabetic nephropathy. With this new concept, ROS assume a greater importance in the pathogenesis of diabetic nephropathy.
Future studies elucidating other downstream-signaling molecules activated by ROS in mesangial and other renal cells will allow
us to understand the final cellular responses to HG, such as proliferation, differentiation, apoptosis, and ECM accumulation.
With this new information, we should be able to develop strategies for a more rational treatment of diabetic nephropathy.