The glomerular basement membrane and mesangial matrix represent highly specialized forms of extracellular matrix (ECM). Synthesized by the intrinsic glomerular cells, this specialized matrix presumably undergoes normal catabolic turnover. During various pathologic states it is possible that unregulated glomerular ECM catabolism could lead to structural damage to these critical elements. In addition, disorders associated with increased matrix accumulation may be in part due to disturbances of the normal matrix catabolic processes. Evidence obtained from other ECM systems, such as bone, has demonstrated that peptide growth factors play an important role in the cellular regulation of ECM metabolism. Glomerular mesangial cells (MC), which are normally embedded within the mesangial matrix area, have been found to be responsive to several peptide growth factors, including Interleukin-1 (IL-1), platelet-derived growth factor (PDFD), and epidermal growth factor (EGF). Previous studies have emphasized the cellular proliferative effects of these factors. Recent observations have indicated that MC secrete several proteins which may be directly involved in the turnover of the glomerular ECM. These include a specific type IV collagenase and a protein closely resembling the tissue inhibitor of metalloproteinases (TIMP). In this proposal experiments are outlined which will examine the potential modulatory effects of four relevant peptide growth factors, (IL-1, PDGF, EGF and transforming growth factor-beta) on the synthesis and regulation of the mesangial cell type IV collagenase and the TIMP protein. These studies will involve specific functional and immunoassays of secreted proteins. In addition, biosynthetic labelling and electrophoretic analysis of intracellular precursors will be performed. The cellular coordination of type IV collagenase and TIMP secretion will be examined at several levels including immunohistochemistry. These studies will hopefully extend our knowledge of the cell biology of the mesangial cell as it relates to peptide growth factors and ECM metabolism thereby allow for a further understanding of the mechanisms leading to glomerular injury.
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