Lefty is a novel member of the transforming growth factor (TGF) supergene family which has the potential to antagonise actions of TGF-beta 1-the main factor driving fibrotic disease in the kidney and in other organs. TGF-beta 1 can induce fibrosis through several mechanisms, including epithelial-mesenchymal transition (EMT) which contributes to myofibroblast accumulation in the renal interstitium. This study examined whether Lefty can antagonise TGF-beta 1 mediated EMT. A rat tubular epithelial cell line (NRK52E) was stably transfected with a Lefty expression plasmid (52E-Lefty) or control plasmid (52E-Control). 52E-Control cells underwent TGF-beta 1 induced EMT with up-regulation of alpha-smooth muscle actin (alpha-SMA), down-regulation of E-cadherin, and transition to an elongated fibroblast-like morphology. In contrast, 52E-Lefty cells were substantially protected from TGF-beta 1 induced EMT. Analysis of signalling pathways showed that 52E-Lefty cells had a marked reduction in TGF-beta 1 induced Smad activity and suppression of the secondary phase of JNK (but not p38) signalling. Treatment of NRK52E cells with a JNK inhibitor was shown to suppress TGF-beta 1 induced EMT. In conclusion, Lefty can antagonise TGF-beta 1 mediated EMT in renal tubular epithelial cells. Lefty may have potential as an anti-fibrotic molecule in the treatment of renal fibrosis. (C) 2010 Elsevier Inc. All rights reserved.