title: TGF-β1 mediates sirolimus and cyclosporine A-induced alteration of barrier function in renal epithelial cells via a noncanonical ERK1/2 signaling pathway.
abstract: The immunosuppressant drugs cyclosporine A (CsA) and sirolimus (SRL) used in combination demonstrated beneficial effects in organ transplantation, but this combination can also result in increased adverse effects. We previously showed that not only CsA treatment but also its combination with SRL decreased paracellular permeability in renal proximal tubular cells by modification of the tight junction proteins, claudins, through ERK1/2 signaling pathway. In this present study, evidence is presented that not only CsA but also the combination of CsA/SRL may have adverse effects on the barrier function of renal proximal cells, at least in part, through the expression of the cytokine transforming growth factor (TGF)-β(1). CsA treatment upregulated TGF-β(1) gene expression and this upregulation was enhanced when CsA and SRL were applied together. Addition of TGF-β(1) (5 ng/ml) altered the barrier function with increased transepithelial electrical resistance (TER) and claudin-1 expression. Use of a TGF-β(1)-blocking antibody or blockage of TGF-β(1) receptor kinase activity with SD208 prevented the CsA- and CsA/SRL-induced increase in TER. No evidence was found in the present studies to indicate that CsA or CsA/SRL treatment activated the TGF-β(1) Smad canonical signaling pathway, whereas addition of TGF-β(1) (5 ng/ml) did activate the Smad pathway. Addition of the ERK1/2 signaling inhibitor U0126 was able to prevent the TGF-β(1)-mediated increase in TER and claudin expression. It is most likely that the CsA- and CsA/SRL-induced increases in TGF-β(1) expression may not be sufficient to trigger the Smad pathway but however may trigger other TGF-β(1) receptor-mediated signaling including the ERK1/2 signaling pathway.
authors: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors: Natalia
authors: N
authors: Martin-Martin
authors: Craig
authors: C
authors: Slattery
authors: Tara
authors: T
authors: McMorrow
authors: Michael P
authors: MP
authors: Ryan
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D062445:Claudin-1; D016572:Cyclosporine / Q000494:pharmacology*; D017097:Electric Impedance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008565:Membrane Proteins / Q000096:biosynthesis; D009570:Nitriles / Q000494:pharmacology; D011621:Pteridines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology*; D051785:Smad Proteins / Q000378:metabolism; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D002070:Butadienes; D062445:Claudin-1; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D009570:Nitriles; D011621:Pteridines; C511004:SD-208; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C113580:U 0126; D016572:Cyclosporine; D020123:Sirolimus