Renal Cell Injury in Diabetes

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DESCRIPTION (provided by applicant): Project Summary. The applicant is completing a post-doctoral fellowship and will assume a position as assistant professor in the tenure track effective 10-1-06. The applicant is applying for this career development award and will be sponsored by two physician scientists with a primary interest in the subject material of this proposal. Both sponsor and co-sponsor are experienced and productive scientists with long standing history of successful graduate students, postdoctoral fellows and junior faculty. Advanced glycation end-products (AGEs) play a central role in the pathogenesis of diabetic complications such as diabetic nephropathy (DN). AGEs stimulate reactive oxygen species (ROS) generation through AGE-specific receptors, which lead to the up-regulation of genes involved in diabetic nephropathy (DN). It has been suggested that ROS generated by the mitochondria electron-transfer chain is the major player in diabetic oxidative stress, however, research in our laboratory find novel NAD(P)H-oxidases, highly expressed in the kidney, to be major sources of ROS in renal hypertrophy and extracellular matrix accumulation (ECM). In preliminary data we show Nox4 localizes to mitochondria as well as plasma membrane. The objective of this grant is to explore the role of AGE-induced oxidative stress in DN. We will first identify the subunits of the NAD(P)H-oxidase(es) that mediate AGE-induced ROS generation which lead to renal hypertrophy and ECM. Secondly, we wish to understand the contribution and cross talk between two major cellular sources of ROS generation, NAD(P)H-oxidases and the mitochondria-electron transfer chain. We will evaluate this novel connection in mesangial cells, the cell of the kidney predominantly involved in hypertrophy and ECM. Finally, in vivo studies will allow us to elucidate the role of NAD(P)H-oxdase(es) and the molecular mechanisms involved in proteinuria, a major complication of DN and an important issue highly relevant for diabetic patients. An attenuation of AGE-induced matrix accumulation and/or protein secretion by delivery of anti-sense NAD(P)H-oxidase injection in the long-term experiments will demonstrate that NAD(P)H-dependent ROS generation contributes not only to the initiation of DN but also to its progression. Our long-term goal is to translate the findings from this research into the discovery of specific inhibitors of ROS generation. The oxdiase will thereby become a primary target for future therapeutic intervention. Our laboratory has the expertise and our University has all the resources available to address the work proposed in this grant. Relevance. Kidney failure is a common complication of diabetes. Our studies will examine oxidative stress induced by modified proteins (Advanced glycation end products-AGEs) that accumulate in all organs as a result of the diabetic environment. Elucidating these events may allow future modulation of the enzymatic complex(es) to prevent oxidative stress implicated in cellular injury in diabetes.