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  • Title: FHL2 promotes tubular epithelial-to-mesenchymal transition through modulating β-catenin signalling.
    Author: Cai T, Sun D, Duan Y, Qiu Y, Dai C, Yang J, He W.
    Journal: J Cell Mol Med; 2018 Mar; 22(3):1684-1695. PubMed ID: 29193729.
    Abstract:
    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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