The cytokine transforming growth factor-B (TGF-B) 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-B 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 HTV-associated nephropathy. TGF-B 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 whatis the cause of the persistent TGF-B overexpression that leads to progressive fibrosis and kidney failure? In the course of our work we have discovered a complex interconnection between TGF-B and the renin-angiotensin system (RAS) in the kidney.The RAS acts to stimulate the production and activation of TGF-B and to increase the expression of TGF-B receptors which greatly enhances TGF-B's fibrotic effects. We hypothesize that continued stimulation of TGF-Jl by the RAS may be a molecular mechanism for the continued overexpression of TGF-fi in kidney diseases. In this application we propose to investigate the molecular interconnections by which the RAS may perpetuate the actions of TGF-B and to explore in vivo therapeutic strategies to block these effects by doing the following: /) Investigate a molecular mechanism by which angiotensin II may up-regulate TGF-fi receptors by analyzing the functional elements of the TGF-fi type I receptor promoter in the kidney, 2) Investigate the possibility that renin orprorenin may be up-stream effectors that, especially in the presence of angiotensin II blockade, induce TGF-J3 overexpression and thus contribute to progressive fibrotic disease and 3) Continue investigation of the role of interactions between the renin-angiotensin system, TGF-ft overexpression and TGF-fi receptor expression in the pathogenesis of fibrosis using a model ofacute 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 mat 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 humanssuffering from kidney disease.
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