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Gefitinib attenuates transforming growth factor-β1-activated mitogen-activated protein kinases and mitogenesis in

San-Cher Chen1, Jinn-Yuh Guh, Tai-Du Lin

  • 1Institute of Biomedical Sciences, National Sun Yat-Sen University, Taiwan, Republic of China.

Translational Research : the Journal of Laboratory and Clinical Medicine
|September 20, 2011
PubMed

Insights

Gefitinib, an EGFR inhibitor, reduces kidney fibrosis by blocking TGF-β1-induced cell growth and collagen production through the EGFR-ERK/p38 pathway in vitro.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Kidney fibrosis involves transforming growth factor-β (TGF-β), TGF-β receptor (TGF-βR), and epidermal growth factor receptor (EGFR).
  • EGFR inhibition shows promise in mitigating kidney fibrosis in animal models.
  • Understanding the molecular mechanisms of EGFR inhibition in renal fibroblasts is crucial.

Purpose of the Study:

  • To investigate the effects and molecular mechanisms of gefitinib on TGF-β1-induced fibroblast responses.
  • To determine gefitinib's impact on cell mitogenesis, cyclin D1 expression, and collagen production in vitro.

Main Methods:

  • Utilized normal rat kidney interstitial fibroblast (NRK-49F) cells.
  • Stimulated cells with TGF-β1 and treated with gefitinib, SB431542, SB203580, and PD98059.
  • Assessed cell mitogenesis, cyclin D1 protein expression, and collagen production.
  • Analyzed signaling pathways including EGFR transactivation, Smad2/3, ERK1/2, and p38 kinase phosphorylation.

Main Results:

  • TGF-β1 increased NRK-49F cell mitogenesis and cyclin D1 expression, and transactivated EGFR.
  • Gefitinib, SB431542, and SB203580 attenuated TGF-β1-induced phosphorylation of ERK1/2 and p38 kinase.
  • Gefitinib and SB431542 inhibited TGF-β1-induced cyclin D1 expression and collagen production.
  • Gefitinib, SB431542, PD98059, and SB203580 attenuated TGF-β1-induced cell mitogenesis.

Conclusions:

  • Gefitinib effectively inhibits TGF-β1-induced cell mitogenesis and collagen production in NRK-49F cells.
  • The mechanism involves the EGFR-ERK1/2/p38 kinase pathway, leading to reduced cyclin D1 expression.
  • Gefitinib demonstrates potential as a therapeutic agent for kidney fibrosis.

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