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ERK, p38, and Smad signaling pathways differentially regulate transforming growth factor-beta1 autoinduction in

Mei Zhang1, Donald Fraser, Aled Phillips

  • 1Institute of Nephrology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN UK. phillipsao@cf.ac.uk.

The American Journal of Pathology
|September 28, 2006
PubMed

Insights

Transforming growth factor-beta1 (TGF-beta1) autoinduction in kidney proximal tubular cells involves independent Smad and MAP kinase pathways. These pathways regulate distinct TGF-beta1 mRNA and protein synthesis steps, crucial for renal fibrosis.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Transforming growth factor-beta1 (TGF-beta1) is a key mediator in progressive renal disease fibrosis.
  • Proximal tubular cells (PTCs) play a significant role in renal fibrosis.
  • The autoinduction mechanism of TGF-beta1 in PTCs requires further elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying TGF-beta1 autoinduction in proximal tubular cells.
  • To identify the signaling pathways involved in TGF-beta1 synthesis regulation.
  • To differentiate the roles of Smad and MAP kinase pathways in TGF-beta1 production.

Main Methods:

  • Treatment of PTCs with TGF-beta1.
  • Analysis of TGF-beta1 mRNA and protein synthesis.
  • Assessment of R-Smad phosphorylation and MAP kinase activation (ERK, p38).
  • Utilized dominant-negative Smad3 (Smad3 DN) and small interfering RNA (siRNA) for Smad3.
  • Employed chemical inhibitors PD98059 (ERK) and SB203580 (p38).
  • Investigated transcription factor activation (AP-1, NF-kappaB).

Main Results:

  • TGF-beta1 stimulation increased TGF-beta1 mRNA and de novo protein synthesis.
  • TGF-beta1 activated R-Smads, ERK, and p38 MAP kinase pathways independently.
  • Smad3 and ERK pathways were essential for TGF-beta1 mRNA upregulation.
  • Smad3 blockade inhibited AP-1 activation; PD98059 inhibited NF-kappaB activation.
  • p38 MAP kinase inhibition reduced de novo TGF-beta1 protein synthesis but not mRNA levels or transcription factor activation.

Conclusions:

  • TGF-beta1 autoinduction in PTCs is a complex process requiring coordinated, independent Smad and non-Smad (MAP kinase) pathways.
  • The Smad pathway regulates TGF-beta1 transcription (via AP-1), while ERK and p38 pathways influence mRNA and protein synthesis, respectively.
  • These findings highlight distinct regulatory roles in TGF-beta1 production, offering potential therapeutic targets for renal fibrosis.

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