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MAPK/AP-1-dependent regulation of PAI-1 gene expression by TGF-beta in rat mesangial cells

Baoliang Guo1, Ken Inoki, Motohide Isono

  • 1Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan.

Kidney International
|August 18, 2005
PubMed
Abstract

Insights

Transforming growth factor-beta (TGF-beta) induces plasminogen activator inhibitor-1 (PAI-1) expression in rat mesangial cells via the mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) pathway. This MAPK/AP-1 requirement is specific to rats, unlike in humans.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-beta) signaling regulates gene expression through receptor-regulated Smads and mitogen-activated protein kinases (MAPKs).
  • Plasminogen activator inhibitor-1 (PAI-1) is a key gene regulated by TGF-beta, but its promoter sequence differs between species.
  • Understanding species-specific mechanisms is crucial for TGF-beta research.

Purpose of the Study:

  • To elucidate the mechanisms of TGF-beta-induced PAI-1 expression in rat mesangial cells.
  • To investigate the roles of MAPKs, Smads, and transcription factors in regulating rat PAI-1 gene expression.
  • To compare TGF-beta signaling pathways in rat versus human systems.

Main Methods:

  • Northern blot analysis for PAI-1 and c-fos mRNA.
  • Immunoblot analysis for MAPK and Smad activation.
  • Electrophoretic mobility shift assay (EMSA) for DNA binding.
  • Luciferase reporter assay for promoter activity.

Main Results:

  • TGF-beta1-induced PAI-1 and c-fos expression were dependent on the ERK/JNK-AP-1 pathway, inhibited by MEK inhibitors.
  • An AP-1-like sequence in the rat PAI-1 promoter was essential for basal and TGF-beta1-induced activity.
  • Smad nuclear translocation and binding to SBE occurred independently of MEK inhibition and did not affect PAI-1 promoter activity.
  • Interferon-gamma (IFN-gamma) inhibited TGF-beta1-induced PAI-1 via the ERK-AP-1 pathway.

Conclusions:

  • MAPK/AP-1 activation is essential for TGF-beta1-induced PAI-1 expression in rat mesangial cells.
  • This reliance on MAPK/AP-1 is a unique characteristic of rat PAI-1 regulation.
  • The findings highlight species-specific differences in TGF-beta signaling pathways.

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