Abstract: FR-PO362

FHL2 Promotes Fibroblast Activation and Kidney Fibrosis Involving the Activation of β-Catenin Signaling

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis


  • Duan, Ying, Nanjing medical university, Nanjing, China
  • Cai, Ting, Nanjing Medical University, NANJING, China
  • Yang, Junwei, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China
  • He, Weichun, Nanjing Medical University, 2nd Affiliated Hospital, Nanjing, China

Four-and-a-half LIM domains protein 2 (FHL2) is an adaptor protein and has been implicated in β-catenin signaling. Previously, we found that FHL2 may mediate TGF-β1-induced tubular epithelial-to-mesenchymal transition through activating β-catenin signaling. The FHL2-positive cells were observed both in renal tubule and interstitium in mice with obstructive nephropathy. However, the potential role and mechanisms for FHL2 in fibroblast activation and kidney fibrosis remains to be clarified.


The regulation and function of FHL2 in TGF-β1-stimulated fibroblast activation were examined in cultured NRK-49F cells. Mice with fibroblast-specific deletion of FHL2 were generated by mating FHL2-floxed mice with S100a4-Cre transgenic mice. Mouse model of kidney fibrosis was established by unilateral ureteral obstruction (UUO).


TGF-β1 induced FHL2 mRNA and protein expression in a time- or dose-dependent manner in cultured cells. Ectopic expression of FHL2 increased α-smooth muscle actin (α-SMA), type I collagen and fibronectin expression, whereas knockdown of FHL2 via small interfering RNA partially suppressed TGF-β1-induced expression of α-SMA, type I collagen and fibronectin. Overexpression of FHL2 led to activation of β-catenin signaling, which is evidenced by an increase in β-catenin nuclear translocation, β-catenin-mediated gene transcription, and expression of β-catenin target genes such as Snail and c-Myc. Treatment with TGF-β1 induced a physical interaction between FHL2 and β-catenin. In vivo, FHL2 was induced and β-catenin was activated in renal interstitial myofibroblasts from mice with obstructive nephropathy. Compared with wild-type littermates, the kidneys with fibroblast-specific ablation of FHL2 exhibited less interstitial extracellular matrix deposition at 2 weeks after UUO.


Our results suggest that FHL2, through activating β-catenin signaling, plays a critical role in mediating TGF-β1-induced fibroblast activation and contributes to the development and progression of kidney fibrosis, and FHL2 could be a potential future therapeutic target for chronic kidney disease.


  • Government Support - Non-U.S.