Upregulation of MMP-2 by all-trans retinoic acid is mediated by TGF-ß1 in cultured rat mesangial cell

Matrix metalloproteinase-2 (MMP-2) degrades basement membrane collagen and its abnormal expression is associated with glomerulonephritis and glomerulosclerosis. All-trans retinoic acid (ATRA) has been indicated as preventing age-related glomerulosclerosis. The results of our study showed that ATRA upregulated expression of MMP-2 mRNA and secretion of MMP-2 proteins, and increased enzymatic activity of MMP-2 in cultured mesangial cell. In addition, ATRA also caused a dose-dependent increase in the secretion of transforming growth factor-ß (TGF-ß1) peptides. Since TGF-ß1 regulated the expression of MMP-2 in mesangial cell, it is possible that TGF- ß1 is involved in ATRA-induced MMP-2 expression. Using antisense TGF-ß1 RNA strategy, antisense TGF-ß1 construct almost completely blocked secretion of active TGF-ß1 peptides in the antisense-bearing transfectants. Northern blot analysis showed that the transfectants treated with 10^-6M ATRA for 72 h neither increased nor decreased the levels of MMP-2 messenger ribonucleic acid (mRNA). Moreover, addition of anti-TGF-ß1 antibodies to mesangial cell in the presence of 10^-6M ATRA reduced ATRA-induced MMP-2 expression dose dependently. These data suggest that TGF-ß1 might be involved in ATRA- induced MMP-2 expression.