FHL2 promotes tubular epithelial-to-mesenchymal transition through modulating
?-catenin signalling
#MMPMID29193729
Cai T
; Sun D
; Duan Y
; Qiu Y
; Dai C
; Yang J
; He W
J Cell Mol Med
2018[Mar]; 22
(3
): 1684-1695
PMID29193729
show ga
?-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 ?-catenin in several other cell types. To
determine whether FHL2 affects ?-catenin signalling and thus is involved in
tubular EMT, we examined its expression and function in the process of
TGF-?1-induced EMT. FHL2 mRNA and protein were induced by TGF-?1 in rat tubular
epithelial cells (NRK-52E), an effect that intracellular Smad signalling was
required. Ectopic expression of FHL2 inhibited E-cadherin and enhanced ?-smooth
muscle actin (?-SMA) and fibronectin expression, whereas knockdown of FHL2
partially restored E-cadherin and reduced ?-SMA and fibronectin induction
stimulated by TGF-?1. Overexpression of FHL2 increased ?-catenin
dephosphorylation (Ser37/Thr41), nuclear translocation and ?-catenin-mediated
transcription and up-regulated expression of ?-catenin target, EMT-related genes,
such as Snail, Twist, vimentin, plasminogen activator inhibitor-1 and matrix
metalloproteinase-7. Conversely, knockdown of FHL2 increased ?-catenin
phosphorylation (Ser33/37/Thr41), decreased its nuclear translocation and
inhibited ?-catenin-mediated transcription and target genes expression. TGF-?1
induced a FHL2/?-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 ?-catenin
activation were positively correlated with FHL2 induction. Collectively, this
study suggests that FHL2, via modulating ?-catenin signalling, may implicate in
regulation of TGF-?1-mediated tubular EMT and could be a potential therapeutic
target for fibrotic kidney disease.
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