HIPK2 attenuates bleomycin-induced pulmonary fibrosis by suppressing the Wnt/β-catenin signaling pathway.

Abstract

The present study aimed to investigate the effect of homeodomain interacting protein kinase 2 (HIPK2) on pulmonary fibrosis and the probable mechanisms. We constructed a mouse model of bleomycin-induced pulmonary fibrosis and up-regulated the expression of HIPK2 in the lung by in vivo transfection. Lung tissues were collected for the detection of mesenchymal markers (α-SMA, collagen I, collagen III) and the expression of β-catenin as assessed by RT-PCR, western blot, and immunohistochemistry. Mouse lung fibroblasts (MLFs) with upregulation or downregulation of HIPK2 were successfully constructed and XAV939 was used to downregulate β-catenin expression. Then, we evaluated the activation of MLFs and the Wnt/β-catenin pathway under various conditions. The results showed that in the bleomycin-induced mouse model group, the lung alveolar structure was severely damaged, the amount of collagen fibers was increased in alveolar speta, and the expression of HIPK2 in the fibrotic area was found to be reduced. After upregulating HIPK2 in the lungs of the mouse fibrosis model we found that pulmonary fibrosis was attenuated and the expression of β-catenin and mesenchymal markers was reduced. The upregulation of HIPK2 inhibited the proliferation and migration of MLFs induced by TGF-β1, promoted apoptosis of MLFs, and reduced the expression of mesenchymal markers and β-catenin. Meanwhile, downregulation of HIPK2 promoted the proliferation and migration of MLFs, inhibited apoptosis, and promoted mesenchymal markers and β-catenin expression. XAV939 treatment of MLFs silencing HIPK2 inhibited their proliferation and activation via silencing HIPK2, promoted apoptosis, and reduced interstitial markers and β-catenin expression. HIPK2 can attenuate bleomycin-induced pulmonary fibrosis by inhibiting the Wnt/β-catenin pathway in mouse lung fibroblasts.