The progressive decline in renal function characteristic of most forms of renal disease is intimately associated with the development of glomerular and interstitial fibrosis. The extent of interstitial fibrosis closely predicts the ultimate clinical outcome in terms of development of end stage renal disease. Progressive interstitial fibrosis may be initiated by multiple factors, including immune injury, hypoxia, reduction in renal mass and diabetes mellitus; however, these insults converge to a final common pathway associated with tubular epithelial cell transdifferentiation to pro- sclerotic myofibroblasts and fibroblasts, This laboratory has focused on the role of specific matrix metalloproteinases in the initiation and perpetuation of the pro-fibrotic transdifferentiation of tubular epithelial cells. Specifically, coordinate expression of two matrix metalloproteinases, gelatinase A and MT1-MMP, appears to drive the transdifferentiation process in vitro and in vivo.
The Specific Aims of this proposal are to define at the transcriptional level, with an emphasis on TGFbeta, common signaling pathways and transcription factors which link gelatinase A and MT1-MMP transcription. Secondly, a transgenic approach will be taken to examine the relationship between gelatinase A and MT1-MMP gene expression in a TGF-beta-driven model of progressive renal fibrosis. Finally, the ability of gelatinase A to directly induce interstitial fibrosis in vivo will be assessed using targeted conditional expression in the transgenic mouse. Taken together, these complementary approaches may provide important new insights into the mechanisms of progressive renal fibrosis and point out specific molecular targets suitable for new forms of therapies of these disabling disorders.
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