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

Am J Physiol Renal Physiol. 2001 Apr;280(4):F628-35. doi: 10.1152/ajprenal.2001.280.4.F628.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Azepines / pharmacology
  • Cytochalasin D / pharmacology
  • Endothelin Receptor Antagonists
  • Endothelin-1 / immunology
  • Endothelin-1 / metabolism
  • Endothelin-2 / immunology
  • Endothelin-2 / metabolism
  • Endothelin-3 / immunology
  • Endothelin-3 / metabolism
  • Endothelins / immunology
  • Endothelins / metabolism*
  • Enzyme Activation / physiology
  • Gene Expression Regulation, Enzymologic
  • Glomerular Mesangium / enzymology*
  • Indoles / pharmacology
  • Male
  • Matrix Metalloproteinase 1 / genetics
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism*
  • Neutralization Tests
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Endothelin A
  • Tissue Inhibitor of Metalloproteinase-2 / genetics
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism


  • Antibodies, Monoclonal
  • Azepines
  • Endothelin Receptor Antagonists
  • Endothelin-1
  • Endothelin-2
  • Endothelin-3
  • Endothelins
  • Indoles
  • Nucleic Acid Synthesis Inhibitors
  • Receptor, Endothelin A
  • Tissue Inhibitor of Metalloproteinase-2
  • FR 139317
  • Cytochalasin D
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 1