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ECM degradation by cultured human mesangial cells is mediated by a PA/plasmin/MMP-2 cascade

W H Baricos1, S L Cortez, S S el-Dahr

  • 1Department of Biochemistry, Tulane Medical School, New Orleans, Louisiana, USA.

Kidney International
|April 1, 1995
PubMed

Insights

Human mesangial cells degrade extracellular matrix via the plasminogen activator/plasmin system. Inhibiting plasmin and matrix metalloproteinases (MMPs) blocks this degradation, highlighting the system's crucial role.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Extracellular Matrix Research

Background:

  • The plasminogen activator/plasmin system is implicated in extracellular matrix (ECM) remodeling.
  • Human mesangial cells play a role in kidney function and ECM dynamics.

Purpose of the Study:

  • To investigate the involvement of the plasminogen activator/plasmin system in ECM degradation by human mesangial cells.
  • To identify the specific components and mechanisms by which mesangial cells degrade ECM.

Main Methods:

  • Culturing human mesangial cells on 125I-labeled ECM (Matrigel) to quantify degradation.
  • Utilizing plasmin inhibitors (alpha-2-antiplasmin, aprotinin) and an MMP inhibitor (TIMP-1).
  • Employing zymography, Northern analysis, Western blotting, and ELISA to detect enzyme activity and expression of key proteins (tPA, uPA, PAI-1, uPAR, MMP-2).

Main Results:

  • ECM degradation was dependent on plasminogen and mesangial cell presence, correlating with plasmin appearance.
  • Plasmin inhibitors completely blocked degradation, while TIMP-1 partially reduced it.
  • Latent MMP-2 was activated in the presence of mesangial cells and plasminogen.
  • Mesangial cells express mRNA for tPA, uPA, PAI-1, and uPAR, with excess PAI-1 over uPA and tPA proteins.
  • Monoclonal antibodies against tPA and uPA significantly reduced ECM degradation.

Conclusions:

  • The plasminogen activator/plasmin system, particularly plasmin, is a key mediator of ECM degradation by human mesangial cells.
  • Both plasmin and matrix metalloproteinases (MMPs) contribute to ECM breakdown, with plasmin playing a dominant role.
  • Human mesangial cells actively regulate ECM degradation through the expression of plasminogen activators and inhibitors.

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