Lefty antagonises TGF-beta1 induced epithelial-mesenchymal transition in tubular epithelial cells.
Lefty is a novel member of the transforming growth factor (TGF) supergene family which has the potential to antagonise actions of TGF-beta1 - the main factor driving fibrotic disease in the kidney and in other organs. TGF-beta1 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-beta1 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-beta1 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-beta1 induced EMT. Analysis of signalling pathways showed that 52E-Lefty cells had a marked reduction in TGF-beta1 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-beta1 induced EMT. In conclusion, Lefty can antagonise TGF-beta1 mediated EMT in renal tubular epithelial cells. Lefty may have potential as an anti-fibrotic molecule in the treatment of renal fibrosis.
Mariasegaram
Mythily
M
Department of Nephrology, Monash University, Monash Medical Centre, Clayton, Vic., Australia.
Tesch
Greg H
GH
Verhardt
Sarah
S
Hurst
Lyn
L
Lan
Hui Y
HY
Nikolic-Paterson
David J
DJ
D000818:Animals; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D055458:Left-Right Determination Factors / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D051381:Rats; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology
D055458:Left-Right Determination Factors; C111386:Lefty1 protein, mouse; D053773:Transforming Growth Factor beta1