PRODUCTION OF METALLOPROTEINASES AND TIMPS BY GLOMERULAR CELLS

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Glomerulosclerosis occurs in a large number of human kidney diseases, including diabetic nephropathy. It consists of the accumulation of extracellular matrix (ECM) within the glomerulus. Sclerosis may be mediated by dysregulation of both synthesis and degradation of ECM. A large family of matrix metalloproteinases as well as tissue inhibitors of metalloproteinase (TIMPs) play a role in the degradative process. Our preliminary work reveals that: 1) normal mouse mesangial cells in culture secrete a 72 kD and a 92 kD gelatinase (type IV collagenase) as well as TIMP1; 2) mesangial cells derived from NOD mice and mice transgenic for bovine growth hormone (bGH) secrete mostly the 72 kD gelatinase; Normal mouse glomeruli contain mRNA coding the 72kD species. This mRNA is increased in mice transgenic for bGH who have sclerotic lesions. TIMP mRNAs are undectable in mouse glomeruli which emphasizes the major phenotypic changes that occur in vivo. In the GH mice the upregulation of the 72KD gelatinase is less prominent than that of type IV collagen. This finding may suggest that there is an imbalance between synthesis and degradation of extracellular matrix in certain forms of glomerulosclerosis. 92kD gelatinase is also being investigated at the mRNA and protein levels, since it appears to increase in response to exposure to pentosan sulfate. This may have important therapeutic applications.