Enhanced expression of membrane type-1 matrix metalloproteinase in mesangial proliferative glomerulonephritis.

Matrix metabboproteina.se-2 (MMP-2, gebatinase A) is involved in the inflammatory and sclerotic events of gbomerular diseases. Newly identified membrane-type matrix metalboprotein- ases (MT-MMP) have been shown to activate specifically proMMP-2. To date, several types of MT-MMP have been cloned; however, their expressions in gbomerular diseases have not been evaluated. To investigate the role of MT-MMP in gb- merular diseases, the gbomerular gene expression and enzymatic activity of MT-MMP were examined during the time course of nephritis induced in rats by anti-Thyl. 1 antibody injection. Both MTI-MMP and MMP-2 mRNA expression increased promi- nently 5 and 10 d after anti-Thyl. 1 antibody injection and de- creased thereafter, as assayed by semiquantitative reverse Iran- scription-PCR. In contrast, there were no remarkable changes in the gene expression of MT2-MMP between normal and diseased tissue, and that of MT3-MMP was not detected in isolated gb- meruli by reverse transcription-PCR analysis. The activation of proMMP-2 as analyzed by gelatin zymography correlated with the gbomerular MT1-MMP gene expression, suggesting that proMMP-2 was activated by MT1-MMP. Protein and mRNA expression of fibronectin, one of the major mesangial matrix proteins and substrate of MMP-2, were also synchronized with MT1-MMP and MMP-2 expression. In situ hybridization re- vealed intense MT1-MMP mRNA expression in the proliferating mesangiab cells. Interestingly, MT1 -MMP gene expression exhib- ited a similar distribution as a-smooth muscle actin expression, which was closely associated with mesangial phenotypic change. These results suggest that among the newly identified MT-MMP, MTI-MMP may play the central role in activation of proMMP-2. Furthermore, the enhancement of MT1-MMP and MMP-2 ex- pression associated with mesangial phenotypic change may con- tribute to the development of anti-Thy 1. 1 antibody-induced gb- merubonephritis and remodeling of extracebbular matrices.