MESANGIAL CELLS FROM TRANSGENIC MICE WITH PROGRESSIVE GLOMERULOSCLEROSIS EXHIBIT STABLE, PHENOTYPIC CHANGES INCLUDING UNDETECTABLE MMP-9 AND INCREASED TYPE-IV COLLAGEN

Mice transgenic for bovine growth hormone (bGH) develop progressive me sangial sclerosis resulting in uremia. Mesangial cells from bGH mice w ere isolated to determine whether the cells maintained a stable phenot ypic change in the synthesis and degradation of extracellular matrix, which contribute to the glomerular lesions in vivo. The bGH mesangial cells were 1.2-fold larger than cells from control mice. They had a 1. 7-fold increase in doubling time, a 7-fold decrease in labeling index (p < 0.0001), and a 2.4- and 2-fold decrease in c-myc (p < 0.05) and i nsulin-like growth factor I gene expression, respectively. Collagen sy nthesis and degradation were studied by PCR, ELISA, and gelatin zymogr aphy. bGH mesangial cell a, collagen IV mRNA levels were increased 2.3 -fold (0.47 +/- 0.25 versus 0.20 +/- 0.09 attomoles/500 cells, p < 0.0 1) whereas secreted collagen IV and collagen IV in the cell lysates we re increased 1.4-fold (25.1 +/- 5 versus 17.2 +/- 4 ng/ml/10(5) cells) and 1.8-fold (30.5 +/- 3 versus 16.7 +/- 3 ng/ml/10(5), p < 0.05), re spectively. There were no differences in collagen I mRNA levels or in the protein content of either the media or cell lysates. We were not a ble to detect metalloproteinase 9 (MMP-9) mRNA expression or MMP-9 pro tein in bGH mesangial cell medium, whereas both mRNA and protein were present in controls. MMP-2 mRNA and enzyme activity in bGH cells were, however, elevated 1.5-fold (p < 0.05) and 2.1-fold (p = 0.05) over co ntrols. Transforming growth factor pi mRNA in bGH cells was 1.6-fold h igher than that of controls (p < 0.05). The data suggest that (a) mesa ngial lesions may result from stable, genetically induced, phenotypic changes in mesangial cells, and (b) alterations of MMP-9 and collagen IV expression by mesangial cells may contribute to an imbalance betwee n extracellular matrix synthesis and degradation and play a critical r ole in the genesis of glomerulosclerosis.