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Tgf-beta auto-induction and connective tissue growth factor expression in human renal tubule epithelial cells

Mark E C Dockrell1, Mysore K Phanish, Bruce M Hendry

  • 1Department of Renal Medicine, King's College London School of Medicine, London, UK.

Nephron. Experimental Nephrology
|June 5, 2009
PubMed
Abstract

Insights

The Ras/MAP kinase pathway, particularly N-Ras, drives transforming growth factor-beta1 (TGFbeta1) auto-induction and connective tissue growth factor (CTGF) expression in kidney cells, contributing to renal fibrosis progression.

Area of Science:

  • Cell biology
  • Molecular biology
  • Renal pathophysiology

Background:

  • Transforming growth factor-beta1 (TGFbeta1) is a key driver of renal fibrosis.
  • TGFbeta1 induces epithelial-mesenchymal transition, inhibits proliferation, and promotes apoptosis in renal cells.
  • TGFbeta1 also stimulates its own production and secondary fibrotic mediators like connective tissue growth factor (CTGF).

Purpose of the Study:

  • To investigate the role of the Ras/MAP kinase pathway in TGFbeta1-mediated effects.
  • To elucidate the specific Ras isoform involved in TGFbeta1 signaling in human renal tubule epithelial cells (HKC).

Main Methods:

  • HKC cells were treated with TGFbeta1 to assess proliferation, apoptosis, and CTGF expression.
  • Activation of Ras/MAP kinase pathway components (ERK1/2, AKT) was measured.
  • Specific antisense oligonucleotides were used to inhibit Ha-Ras, Ki-Ras, and N-Ras.
  • The MEK inhibitor PD 98059 was used to assess pathway dependence.

Main Results:

  • TGFbeta1 inhibited HKC cell proliferation and induced apoptosis.
  • TGFbeta1 rapidly increased phospho-ERK1/2 and phospho-AKT levels in a dose-dependent manner.
  • TGFbeta1-induced CTGF expression and TGFbeta1 auto-induction were dependent on MEK and specifically N-Ras.
  • Inhibition of N-Ras significantly reduced TGFbeta1 auto-induction and CTGF expression.

Conclusions:

  • The Ras/MAP kinase pathway, specifically N-Ras, is crucial for TGFbeta1 auto-induction in renal tubule epithelial cells.
  • N-Ras mediates TGFbeta1-induced CTGF expression, a key factor in renal fibrosis.

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