Many renal diseases proceed to glomerular destruction through processes marked by mesangial expansion, intraglomerular cellular proliferation, and ultimately, glomerular sclerosis. Though initiating events vary from one disease process to another, similarities in histopathologic features suggest that disparate processes converge upon common cellular mechanisms to promote glomerular scar formation. Further, progression of glomerular scarring occurs in glomeruli that appear unaffected by primary renal insults. The common features of destructive glomerular scar formation emphasize the importance of identifying the biochemical mediators of shared events in defined models of renal injury. Recent data show that several growth factors, including PDGF, IL-1 and TGF-beta, have dramatic effects upon both proliferation and extracellular matrix production by cultured cells, including cells of the renal glomerulus. The studies proposed in this application are aimed at defining the role that local growth factor expression by cells of the glomerulus plays in mediating glomerular scarring in two defined models of renal injury: a) the remnant kidney and b) transplant rejection. The regulation of expression of these growth factors will be characterized in cell culture, glomerular culture and intact organ situations. Levels of growth factor mRNA will be used as an index of local expression and correlated with markers for local glomerular responses to growth factor stimulation, including induction of mRNAs for growth factor responsive proto-oncogenes and extracellular matrix constituents. These studies will provide insight about the importance of local growth factor production in mediating glomerular pathology in remnant and transplantation rejection models.
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