The cytokine transforming growth factor-beta (TGF-beta) is a key biological mediator of extracellular matrix deposition in health and in fibrotic diseases, especially of the kidney. We have demonstrated a central role for TGF-beta in the pathogenesis of experimental and/or human forms of acute and chronic glomerulonephritis, diabetic nephropathy, hypertensive nephropathy, acute and chronic allograft rejection, cyclosporine nephropathy and HIV-associated nephropathy. TGF-beta is also implicated in numerous fibrotic disorders involving other tissues and organs and is considered to be a principal target for designing novel therapeutic agents to block fibrotic disease. An important question is what is the cause of the persistent TGF-beta overexpression that leads to progressive fibrosis and kidney failure? In the course of our work we have discovered a complex interconnection between TGF-beta and the renin-angiotensin system (RAS) in the kidney. The RAS acts to stimulate the production and activation of TGF-beta and to increase the expression of TGF-beta receptors which greatly enhances TGF-beta's fibrotic effects. We hypothesize that continued stimulation of TGF-beta by the RAS may be a molecular mechanism for the continued overexpression of TGF-beta in kidney diseases. In this application we propose to investigate the molecular interconnections by which the RAS may perpetuate the actions of TGF-beta and to explore in vivo therapeutic strategies to block these effects by doing the following: 1) Investigate a molecular mechanism by which angiotensin II may up-regulate TGF-beta receptors by analyzing the functional elements of the TGF-beta type I receptor promoter in the kidney, 2) Investigate the possibility that renin or prorenin may be up-stream effectors that, especially in the presence of angiotensin II blockade, induce TGF-beta overexpression and thus contribute to progressive fibrotic disease and 3) Continue investigation of the role of interactions between the renin-angiotensin system, TGF-beta overexpression and TGF-beta receptor expression in the pathogenesis of fibrosis using a model of acute glomerulonephritis and to compare the findings with parallel studies in a model of chronic glomerulonephritis. The significance of this application is that it will apply new knowledge and technology to an area of investigation that is directly relevant to improved understanding of the pathogenesis of kidney fibrosis and will likely provide insights that suggest new therapeutic strategies to prevent progressive kidney failure in humans suffering from kidney disease.
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