PATHOLOGY OF GLOMERULAR MATRIX METABOLISM

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Progressive glomerulosclerosis leading to end stage renal failure is a unifying feature of most forms of chronic glomerular disease, and an extensive body of literature has documented the central role of the intrinsic mesangial cell in the complex biologic events which characterize the sclerotic process. This laboratory has focused on the role of a specific matrix metalloproteinase, the 72 kDa gelatinase A (also denoted matrix metalloproteinase 2, MMP-2) ina the evolution of glomerular injury. While normally quiescent and non-proliferative, the mesangial cell acquires during inflammatory states (and in cultaure) a characteristic spectrum of features which may be defined as the "inflammatory phenotype." The acquisition of this inflammatory phenotype is directly coupled with high level synthesis of MMP-2. In recent studies outlined in detail in this proposal, we demonstrated that MMP-2 acts directly upon the synthesizing cells and is critical for the development and maintenance of the inflammatory phenotype. Thus, the fundamental hypothesis of our studies is that persistent mesangial synthesis of MMP-2 is a common feature of the response to inflammatory injury which facilitates the evolution to the sclerotic state. Given the central role proposed for MMP-2 int he development of the mesangial inflammatory phenotype, a deeper understanding of the factos controlling high level MMP-2 synthesis and the mechanisms whereby this enzyme interacts with mesangial cells is warranted. In this regard, the transcriptional regulation of MM{P-2 synthesis by mesangial cells is distinctive and we have been able to identify a strong mesangial cell-specific enhancer element which may dictate the high level expression of MMP-2 characteristic of the inflammatory phenotype. Secondly, evidence gathered from this and other laboratories has indicated that specific plasma membrane MMP-2 binding proteins exist, which may control the interaction of the enzyme with the surrounding extracellular matrix. These observations provide the basis for the following Specific Aims of this proposal: 1. To clone and characterize the specific mesangial cell MMP-2 binding protein which regulates the interaction of the enzyme with the surrounding extracellular matrix; and 2. to characterize the transcriptional regulatory mechanisms involved in the control of high level mesangial cell synthesis of MMP-2 representative of the inflammatory phenotype. The proposed studies are complementary in approach, dealing with the issue of MMP-2 transcriptional regulation by mesangial cells within the context of the inflammatory phenotype and the means by which this enzyme modulates mesangial cellular behavior through specific membrane interactions.