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Role for TGF- in Cyclosporine-Induced Modulation of Renal Epithelial Barrier Function

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

Address correspondence to: Dr. Michael P. Ryan, Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. Phone: +353-1-7166549; Fax: +353-1-71612157; E-mail: michael.p.ryan{at}ucd.ie

Received for publication May 25, 2006. Accepted for publication March 12, 2007.

It was previously shown that cyclosporine A (CsA) increases transepithelial resistance in MDCK cells. Activation of the extracellular signal–regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) cascade seems to be pivotal to the CsA-induced increase in transepithelial electrical resistance (TER). This study examined the role played by TGF- in mediating the CsA-induced activation of ERK1/2 and the resulting increase in TER in MDCK cells. Paracellular permeability across MDCK monolayers after various treatments was assessed by measurement of TER. TGF- secretion was measured by Western blot and ELISA. Activation of the ERK1/2 pathway and tight junction protein expression were also assessed by Western blot analysis. CsA increased production and secretion of TGF- and expression of the TGF- receptor II. Exogenous addition of TGF-1 activated ERK1/2 and increased TER across MDCK monolayers, both of which were attenuated by the MEK inhibitor U0126. Neutralizing antibodies against TGF-1 and the TGF- receptor II significantly reduced the CsA-induced increase in TER. Both CsA and TGF-1 increased expression of tight junction proteins claudin-1 and zonula occludens 2. Inhibition of the p38 MAPK pathway also attenuated the TGF-1–induced increase in TER. The results presented here suggest that the CsA-induced modulation of paracellular permeability may be mediated, at least in part, by an increase in TGF- production.

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J. Am. Soc. Nephrol. 2007 18: 1617-1618. [Full Text] [PDF]

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