Pathobiology of Renal Matrix Metabolism

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Interstitial fibrosis and tubular atrophy are the hallmarks of all forms of progressive renal fibrosis. This laboratory has focused over the past decade on the role of specific matrix metalloproteinases (MMP-2 and MT1-MMP) in this process. MMP-2, in conjunction with MT1-MMP, is sufficient to induce the conversion of the polarized epithelial cell to a fibroblastic phenotype, a process termed epithelial mesenchymal transition (EMT). Quantitatively, EMT, in conjunction with activation and expansion of the interstitial fibroblast population, is a major contributor to tubular atrophy and progressive renal fibrosis. In vitro, EMT is driven by a diverse number of cytokines and environmental factors; however, we have postulated that renal EMT represents a metastable state driven by three dominant transcriptional networks: TGF-beta/Smad; E cadherin/ beta-catenin/Wnt/LEF/TCF; and MAPK/ERK signaling cascades. We have identified both MMP-2 and MT1-MMP as transcriptional targets of the MAPK/ERK signaling cascades and determined that a specific AP-1 complex component, Fra-2, is sufficient to drive the process of EMT in vitro. The primary hypothesis of this proposal is that sustained MAPK/ERK signaling, with enhanced generation of Fra-2, drives the transcription of a defined cohort of genes required for renal EMT. The approaches to this problem include three Specific Aims proposing to characterize, using microarray analysis, Fra-2-regulated genes in a series of clonal populations of epithelial cells displaying a range of epithelial to mesenchymal features. The functional significance of identified genes will be validated using in vitro and in vivo approaches, including a unique model of renal EMT generated by the transgenic expression of active MMP-2 in the renal proximal tubule. Finally, the ability of Fra-2, alone, to induce EMT in vivo will be tested by the transgenic proximal tubule expression of this transcription factor. These studies are designed to identify those gene sets required for renal EMT and thereby hopefully provide new therapeutic targets for the treatment of renal disease.