Endothelin is a potent inhibitor of matrix metalloproteinase-2 secretion and activation in rat mesangial cells

We examined the effects of endothelin (ET) on the activity of matrix metall oproteinase-2 (MMP-2) in cultured MCs. Addition of the ETA receptor antagon ists or neutralizing anti-endothelin antibody into MC cultures markedly aug mented the secretion and activation of MMP-2. On the contrary, addition of the exogenous ET-1 into MC culture significantly inhibited the synthesis of MMP-2 in both basal and cytokines (tumor necrosis factor-alpha and interfe ron-gamma) plus lipopolysaccharide-stimulated conditions. Furthermore, pret reatment of cells with exogenous ET-1 obviously prevented cytochalasin D-el icited activation of MMP-2, an effect that was completely abolished by ETA receptor antagonist, FR139317. In addition, ET-1 was found to be able to su ppress the expression of membrane type-1 MMP (MT1-MMP) and promote the conv ersion of tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) from cell associated form to secreted form. The addition of recombinant TIMP-2 into the culture abrogated dose-dependently the cytochalasin D-elicited activati on of MMP-2. These results suggest that ET is a potent inhibitor of MMP-2 s ecretion and activation in MCs. These novel findings may help us understand the subtle regulation of the synthesis and activation of MMP-2 in MCs. It also provides us with further insight into the pathophysiological mechanism s involving ET in the regulation of matrix turnover in glomerulus.