The mechanisms mediating kidney damage in diabetes likely stem from chronic hyperglycemia; however, the steps involved are not completely understood. Our main hypothesis is that a high ambient glucose level, independent of genetic and hemodynamic factors, exerts a powerful influence on renal cell growth and extracellular matrix biosynthesis in tissue culture. An exciting finding has been the elucidation that Transforming Growth Factor-Beta (TGF-Beta) is an autocrine mediator of many of the renal effects of high glucose. The specific objective of this proposal are to focus on two major aspects of the effects of high glucose on renal glomerular mesangial cells: the modulation of key proteins which regulate transcription, synthesis and bioactivity of TGF- Beta; and the high glucose-induced perturbations in growth factor- mediated cellular signaling and the role of different protein kinase C isozymes. In vivo correlates will be sought by examining kidney expression and cell localization of TGF-Beta in experimental DN in rodents, and attempt to intercept renal TGF-Beta in vivo using neutralizing anti-TGF-Beta antibodies. The significance of these studies is that they will provide a detailed mechanistic understanding of the harmful effects of high glucose concentration on the kidney, and also pave the way for designing innovative means of prevention of DN, even when glucose control is suboptimal.
