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Role for TGF-beta in cyclosporine-induced modulation of renal epithelial barrier function

Gemma Feldman1, Breda Kiely, Natalia Martin

  • 1Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.

Journal of the American Society of Nephrology : JASN
|April 27, 2007
PubMed

Insights

Cyclosporine A (CsA) increases cell layer electrical resistance by boosting TGF-beta production, which activates the ERK1/2 pathway. This mechanism influences tight junction proteins and paracellular permeability in MDCK cells.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Physiology

Background:

  • Cyclosporine A (CsA) is known to increase transepithelial electrical resistance (TER) in Madin-Darby canine kidney (MDCK) cells.
  • The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) pathway is implicated in CsA-induced TER increases.

Purpose of the Study:

  • To investigate the role of transforming growth factor-beta (TGF-beta) in mediating CsA-induced ERK1/2 activation and TER elevation in MDCK cells.
  • To elucidate the signaling pathways involved in CsA's effect on paracellular permeability.

Main Methods:

  • Transepithelial electrical resistance (TER) measurements to assess paracellular permeability.
  • Western blot and ELISA to quantify TGF-beta secretion and protein expression (ERK1/2, tight junction proteins).
  • Inhibition studies using MEK inhibitor (U0126), p38 MAPK inhibitor, and neutralizing antibodies against TGF-beta1 and its receptor.

Main Results:

  • CsA treatment increased TGF-beta production and secretion, along with TGF-beta receptor II expression.
  • Exogenous TGF-beta1 mimicked CsA effects by activating ERK1/2 and increasing TER, which were blocked by U0126.
  • Neutralizing antibodies against TGF-beta1/receptor II attenuated CsA-induced TER increases.
  • Both CsA and TGF-beta1 enhanced expression of tight junction proteins claudin-1 and zonula occludens 2.
  • Inhibition of p38 MAPK partially blocked TGF-beta1-induced TER increase.

Conclusions:

  • The CsA-induced increase in TER and modulation of paracellular permeability in MDCK cells are, at least partly, mediated by enhanced TGF-beta production.
  • The TGF-beta/ERK1/2 signaling axis plays a significant role in CsA's effects on epithelial barrier function.

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