FHL2 promotes tubular epithelial-to-mesenchymal transition through modulating β-catenin signalling.
FHL2 promotes tubular epithelial-to-mesenchymal transition through modulating β-catenin signalling.
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FHL2 通过调节 β-catenin 信号传导促进肾小管上皮间质转化
DOI：
10.1111/jcmm.13446
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发表时间：
2018-03
影响因子：
5.3
通讯作者：
He W
中科院分区：
文献类型：
--
作者：
Cai T;Sun D;Duan Y;Qiu Y;Dai C;Yang J;He W
β - Catenin信号在调节小管上皮-间充质转化（EMT）中起重要作用，这是驱动肾纤维化不可或缺的程序。作为一种适配器蛋白，4½LIM结构域蛋白2 （FHL2）在其他几种细胞类型中作为β -连环蛋白的共同调节剂。为了确定FHL2是否影响β - catenin信号传导从而参与管状EMT，我们检测了其在TGF - β1诱导的EMT过程中的表达和功能。TGF‐β1在大鼠小管上皮细胞（NRK‐52E）中诱导FHL2 mRNA和蛋白，这是细胞内Smad信号传导所必需的。异位表达FHL2抑制E - cadherin，增强α - SMA和纤维连接蛋白的表达，而敲低FHL2部分恢复E - cadherin，减少TGF - β1刺激的α - SMA和纤维连接蛋白的诱导。FHL2的过表达增加了β - catenin去磷酸化（Ser37/Thr41）、核易位和β - catenin介导的转录，并上调了β - catenin靶基因、EMT相关基因的表达，如Snail、Twist、vimentin、纤溶酶原激活物抑制剂- 1和基质金属蛋白酶- 7。相反，敲低FHL2增加β - catenin磷酸化（Ser33/37/Thr41），减少其核易位，抑制β - catenin介导的转录和靶基因表达。TGF‐β1在NRK‐52E细胞中诱导FHL2/β‐catenin相互作用，特别是在细胞核中。在梗阻性肾病小鼠模型中，FHL2 mRNA和蛋白呈时间依赖性诱导，肾β -连环蛋白激活的程度和模式与FHL2诱导呈正相关。总的来说，本研究表明FHL2通过调节β -连环蛋白信号传导，可能参与TGF - β1介导的小管EMT的调节，并可能成为纤维化肾病的潜在治疗靶点。
β‐Catenin signalling plays an important role in regulating tubular epithelial‐to‐mesenchymal transition (EMT), an indispensable programme for driving renal fibrosis. As an adapter protein, four and a half LIM domain protein 2 (FHL2) acts as a coregulator of β‐catenin in several other cell types. To determine whether FHL2 affects β‐catenin signalling and thus is involved in tubular EMT, we examined its expression and function in the process of TGF‐β1‐induced EMT. FHL2 mRNA and protein were induced by TGF‐β1 in rat tubular epithelial cells (NRK‐52E), an effect that intracellular Smad signalling was required. Ectopic expression of FHL2 inhibited E‐cadherin and enhanced α‐smooth muscle actin (α‐SMA) and fibronectin expression, whereas knockdown of FHL2 partially restored E‐cadherin and reduced α‐SMA and fibronectin induction stimulated by TGF‐β1. Overexpression of FHL2 increased β‐catenin dephosphorylation (Ser37/Thr41), nuclear translocation and β‐catenin‐mediated transcription and up‐regulated expression of β‐catenin target, EMT‐related genes, such as Snail, Twist, vimentin, plasminogen activator inhibitor‐1 and matrix metalloproteinase‐7. Conversely, knockdown of FHL2 increased β‐catenin phosphorylation (Ser33/37/Thr41), decreased its nuclear translocation and inhibited β‐catenin‐mediated transcription and target genes expression. TGF‐β1 induced a FHL2/β‐catenin interaction in NRK‐52E cells, especially in the nuclei. In a mouse model of obstructive nephropathy, FHL2 mRNA and protein were induced in a time‐dependent fashion, and the extent and pattern of renal β‐catenin activation were positively correlated with FHL2 induction. Collectively, this study suggests that FHL2, via modulating β‐catenin signalling, may implicate in regulation of TGF‐β1‐mediated tubular EMT and could be a potential therapeutic target for fibrotic kidney disease.
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82.9
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