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PPARgamma ligand attenuates PDGF-induced mesangial cell proliferation: role of MAP kinase

Siddhartha S Ghosh1, Todd W B Gehr, Shobha Ghosh

  • 1Division of Nephrology, MCV Campus, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

Kidney International
|June 6, 2003
PubMed
Abstract

Insights

Peroxisome proliferator-activated receptor gamma (PPARgamma) activators, like ciglitazone, inhibit mesangial cell proliferation by impacting MAPK signaling and cell cycle proteins. This suggests PPARgamma activation is a potential therapeutic target for renal diseases.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • Mesangial cell proliferation is central to renal disease pathogenesis.
  • Platelet-derived growth factor (PDGF) is a key inducer of mesangial cell proliferation.
  • Mitogen-activated protein kinase (MAPK) signaling pathways regulate mesangial cell proliferation.

Purpose of the Study:

  • To investigate whether peroxisome proliferator-activated receptor gamma (PPARgamma) activators inhibit mesangial cell proliferation.
  • To determine if PPARgamma activators modulate the MAPK pathway and cell cycle regulatory proteins.

Main Methods:

  • Mouse mesangial cells were stimulated with PDGF.
  • The effect of ciglitazone (a PPARgamma activator) on cell proliferation was measured.
  • Western blot analysis and transfection studies were used to examine MAPK and cell cycle protein regulation.

Main Results:

  • Ciglitazone dose-dependently inhibited PDGF-induced mesangial cell proliferation.
  • The inhibitory effect was mediated through PPARgamma activation.
  • Ciglitazone inhibited serum response element (SRE) activation, c-fos expression, cyclin D1, p21, and p27 expression.
  • Extracellular signal-regulated protein kinase (ERK) activation was not affected by ciglitazone.
  • A MAP kinase kinase (MEK) inhibitor potentiated ciglitazone's antiproliferative effect.

Conclusions:

  • PPARgamma activation inhibits mesangial cell growth by targeting MAPK signaling and cell cycle proteins.
  • MAPK pathway modulation and cell cycle regulation are key mechanisms for PPARgamma's antiproliferative action.
  • Combined therapy with PPARgamma activators and MAPK inhibitors may enhance therapeutic outcomes in renal diseases.

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