Department of Nephrology, Monash University, Monash Medical Centre, Clayton, Vic., Australia.
Biochem Biophys Res Commun. 2010 Mar 19;393(4):855-9. doi: 10.1016/j.bbrc.2010.02.098. Epub 2010 Feb 18.
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.
Lefty 是转化生长因子 (TGF) 超基因家族的一个新成员，具有拮抗 TGF-β1 作用的潜力——TGF-β1 是导致肾脏和其他器官纤维化疾病的主要因素。TGF-β1 可以通过几种机制诱导纤维化，包括上皮-间充质转化 (EMT)，这有助于肌成纤维细胞在肾脏间质中的积累。本研究探讨了 Lefty 是否可以拮抗 TGF-β1 介导的 EMT。用 Lefty 表达质粒 (52E-Lefty) 或对照质粒 (52E-Control) 稳定转染大鼠肾小管上皮细胞系 (NRK52E)。52E-Control 细胞在 TGF-β1 诱导下发生 EMT，α-平滑肌肌动蛋白 (α-SMA) 上调，E-钙黏蛋白下调，并向拉长的成纤维细胞样形态转变。相比之下，52E-Lefty 细胞在很大程度上免受 TGF-β1 诱导的 EMT。信号通路分析表明，52E-Lefty 细胞中 TGF-β1 诱导的 Smad 活性显著降低，JNK（而非 p38）信号的次级阶段受到抑制。用 JNK 抑制剂处理 NRK52E 细胞可抑制 TGF-β1 诱导的 EMT。总之，Lefty 可以拮抗肾小管上皮细胞中 TGF-β1 介导的 EMT。Lefty 可能有潜力作为治疗肾纤维化的抗纤维化分子。
