STUDIES OF GLOMERULAR CELLS DERIVED FROM NORMAL AND TRANSGENIC MICE

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Glomerulosclerosis is characterized by increased cell and extracellular matrix turnover and is the leading cause of renal failure in the US. We have developed lines of the three indigenous mouse glomerular cell types: epithelial, endothelial and mesangial cells. We chose mice because of the availability of considerable background genetic information. We characterized the biosynthetic capabilities of cells isolated from normal and transgenic mice with chronic progressive renal diseases. All three cell types express type IV collagen alpha chain mRNAs. Mesangial cells express high levels of 1-5 type IV collagen chains as well as types I and VI collagens. 3 type IV collagen predominates in endothelial cells. Endothelial cells and epithelial cells express neither types VI or I collagen. Thus, each cell type has the potential to make a unique contribution to development of glomerulosclerosis. We isolated cells from mice which carry a transgene coding for bovine growth hormone (bGH), since these mice have a diffuse and progressive form of glomerulosclerosis leading to death in uremia. The bGH mesangial cells have decreased cell turnover, increased alpha-1 type IV collagen mRNA levels (as well as increased type IV collagen secretion), and increased transforming growth factor mRNA levels. They express both GH receptor and bGH mRNA by PCR analysis. The transgene contains a metallothionein promoter which is activated by zinc. After zinc treatment there is an increase in GH mRNA and the corresponding peptide is detectable. These data show that glomerulosclerosis induces a stable phenotypic change in mesangial cells. These effects may explain observations suggesting that GH is an important permissive factor in the development of glomerulosclerosis in animal models, and possibly in man.