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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
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ERK-dependent signaling pathway and transcriptional factor Ets-1 regulate matrix metalloproteinase-9 production in

Senyan Liu1, Yan Liang, Haichang Huang

  • 1Division of Nephrology, Peking University First Hospital, Beijing, China.

Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology
|November 23, 2005
PubMed

Insights

Transforming growth factor beta1 (TGFbeta1) significantly increases matrix metalloproteinase-9 (MMP-9) in podocytes via the ERK1/2 pathway. This MMP-9 elevation may contribute to glomerular basement membrane damage and glomerulosclerosis.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Biology

Background:

  • Unregulated synthesis of glomerular basement membrane (GBM) components, extracellular matrix (ECM) proteins, or secretion of ECM-degrading enzymes like matrix metalloproteinases (MMPs) by podocytes can cause GBM damage.
  • Podocyte dysfunction is implicated in various kidney diseases, including glomerulosclerosis.

Purpose of the Study:

  • To investigate the effects of transforming growth factor beta1 (TGFbeta1) on gelatinase production in cultured murine podocytes.
  • To elucidate the underlying molecular mechanisms of TGFbeta1-induced MMP production in podocytes.

Main Methods:

  • Cultured murine podocytes were treated with TGFbeta1.
  • MMP-2 and MMP-9 secretion and mRNA levels were analyzed.
  • Activation of Smad2 and extracellular signal-regulated kinases (ERK1/2) pathways was assessed.
  • Inhibition of signaling pathways using Staurosporine and PD98059 was performed.
  • Protein levels of the transcriptional factor Ets-1 were measured.

Main Results:

  • TGFbeta1 potently induced MMP-9 secretion in a dose- and time-dependent manner, with minimal effect on MMP-2.
  • TGFbeta1 upregulated MMP-9 mRNA but not TIMP-1 mRNA levels.
  • TGFbeta1 activated both Smad2 and ERK1/2 pathways.
  • Inhibition of ERK1/2, but not Smad2, abolished TGFbeta1-stimulated MMP-9 secretion and mRNA expression.
  • TGFbeta1 increased Ets-1 protein levels, which was dependent on ERK1/2 activation.

Conclusions:

  • TGFbeta1 induces MMP-9 production in podocytes primarily through the ERK1/2 MAPK pathway.
  • Increased MMP-9 activity may play a role in GBM damage in response to inflammatory factors.
  • These findings suggest a mechanism linking inflammatory factors to glomerulosclerosis via podocyte-derived MMP-9.

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