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.
Department of Cellular Physiology, Institute of Nephrology, Niigata University School of Medicine, Niigata 951--8510, Japan.
J
J
Yao
T
T
Morioka
B
B
Li
T
T
Oite
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