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 metalloproteinase-2 (MMP-2) in cultured MCs. Addition of the ET(A) receptor antagonists or neutralizing anti-endothelin antibody into MC cultures markedly augmented 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 interferon-gamma) plus lipopolysaccharide-stimulated conditions. Furthermore, pretreatment of cells with exogenous ET-1 obviously prevented cytochalasin D-elicited activation of MMP-2, an effect that was completely abolished by ET(A) receptor antagonist, FR139317. In addition, ET-1 was found to be able to suppress the expression of membrane type-1 MMP (MT1-MMP) and promote the conversion 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 activation of MMP-2. These results suggest that ET is a potent inhibitor of MMP-2 secretion 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 mechanisms involving ET in the regulation of matrix turnover in glomerulus.
Yao
J
J
Department of Cellular Physiology, Institute of Nephrology, Niigata University School of Medicine, Niigata 951--8510, Japan.
Morioka
T
T
Li
B
B
Oite
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000276:immunology / Q000378:metabolism; D019333:Endothelin-2 / Q000276:immunology / Q000378:metabolism; D019334:Endothelin-3 / Q000276:immunology / Q000378:metabolism; D016232:Endothelins / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D005920:Glomerular Mesangium / Q000201:enzymology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D009500:Neutralization Tests; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D016232:Endothelins; D007211:Indoles; D019384:Nucleic Acid Synthesis Inhibitors; D044022:Receptor, Endothelin A; D019716:Tissue Inhibitor of Metalloproteinase-2; C079574:FR 139317; D015638:Cytochalasin D; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1