An emerging body of data links sclerotic renal diseases and mesangial cell proliferation. These diseases may range from acute antibody medicated disorders to the sclerosis associated with 5/6th nephrectomy to even the most indolent and slowly progressive diseases such as diabetic nephropathy. In each of these disorders, there is evidence of mesangial cell proliferation and elaboration of abnormal amounts of extracellular matrix. Associated with these changes is the well known elaboration of TGF-B, and as they describe herein, the elaboration of the matrix metalloproteinase MMP-2 (the 72 kDa type IV collagenase). In vitro experiments with a highly proliferative mesangial cell line indicate that MMP-2 is a potent and very specific growth factor for mesangial cells. Its elimination through antisense techniques dramatically reverts these highly proliferative cells to quiescence. We have developed potent genetic means; catalytic ribozymes, and effective in vivo gene delivery techniques which allow us to study the effect of modulating MMP-2 production (and TGF-B receptor function) on the behavior of single identified mesangial cells in vivo. The hypothesis to be tested is that MMP-2 elaboration may be a central control point through which mesangial cell proliferation in vivo may be modulated. The means used are retroviral gene transfer to catalytic ribozymes to mesangial cells in vivo.
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