The incidence of end stage renal disease (ESRD), which is largely due to diabetes and hypertension, has increased markedly. African Americans, who experience more diabetes and hypertension, suffer excessive rates of ESRD. The goal of this project is to detect early markers of nephropathy in a cohort of young adult African American men and women. The project is based on the concept that oxidative stress activates aberrant regulatory pathways to renal and vessel injury. Hypertension and diabetes are two disorders that induce oxidative stress from increased blood pressure (BP) and from hyperglycemia. Our preliminary data indicate that early changes in glucose tolerance may activate factors that contribute to tissue injury. Pilot data show that urinary excretion of F2 isoprostane, a marker of oxidative stress, and the tissue cytokine transforming growth factor-beta (TGF-Beta) increase markedly following modest hyperglycemia. The vasoactive peptide endothelin-1 (ET-1) is higher and urinary excretion of TGF-Beta is greater in subjects with impaired glucose tolerance (IGT) compared to those with normal glucose tolerance (NGT). To examine the oxidative stress concept this project is designed to test the hypothesis: Relative hyperglycemia, emanating from insulin resistance with deterioration in glucose tolerance, imposes oxidative stress to renal tissue and mediates an increase in activity of TGF-Beta and ET-1, with resultant renal tissue injury expressed by an increase in urinary albumin excretion (UAE).
Our specific aims are to 1) Verify the change in glucose tolerance within a previously examined African American cohort now aged 38-43 years; 2) Determine if markers of oxidative stress can be detected in this cohort; 3) Determine if there is increased expression of TGF-Band ET-1 that is linked with deterioration in glucose tolerance; and 4) Determine if evidence of renal tissue injury (UAE) corresponds with F2 isoprostane excretion, TGF-B activity or ET-1 activity. We will reexamine a well characterized cohort of African American men and women. Measurements include an oral glucose tolerance test and assays for F2 isoprostane, TGF-Beta, ET-1, and UAE. In addition to analysis of newly obtained data, we will also utilize the previously obtained data from this cohort to test the overall theoretical model. The advantage of longitudinal assessment enables us to identify specific parameters that are predictive of an accelerated pathway for renal disease. The results of this project may contribute to improved methods for early detection and prevention of nephropathy due to type 2 diabetes, as well as the development of more specific therapeutic targets for this high risk minority population.
Showing the most recent 10 out of 25 publications
