1. Academic Validation
  2. Salt-inducible kinase 2 (SIK2) inhibitor ARN-3236 attenuates bleomycin-induced pulmonary fibrosis in mice

Salt-inducible kinase 2 (SIK2) inhibitor ARN-3236 attenuates bleomycin-induced pulmonary fibrosis in mice

  • BMC Pulm Med. 2022 Apr 11;22(1):140. doi: 10.1186/s12890-022-01940-0.
Liangneng Zou  # 1 Dequn Hong  # 2 Kecong Li 3 Bingyuan Jiang 4
Affiliations

Affiliations

  • 1 Department of General Medicine, The Fifth Hospital of Xiamen, 101 Min'an Road, Maxiang, Xiang'an, Xiamen, 361101, Fujian, People's Republic of China.
  • 2 Department of Emergency, The Fifth Hospital of Xiamen, 101 Min'an Road, Maxiang, Xiang'an, Xiamen, 361101, Fujian, People's Republic of China.
  • 3 The Affiliated Second Hospital of Xiamen Medical College, 566 Shengguang Road, Ji'mei, Xiamen, 361000, Fujian, People's Republic of China. [email protected].
  • 4 Critical Care Medicine, The Fifth Hospital of Xiamen, 101 Min'an Road, Maxiang, Xiang'an, Xiamen, 361101, Fujian, People's Republic of China. [email protected].
  • # Contributed equally.
Abstract

Background: Pulmonary fibrosis is a fatal lung disease with complex pathogenesis and limited effective therapies. Salt-inducible kinase 2 (SIK2) is a kinase that phosphorylates CRTCs and regulates many physiological processes. However, the role of SIK2 on pulmonary fibrosis remains unclear, and whether SIK2 Inhibitor can attenuate pulmonary fibrosis is unknown.

Method: We subjected human fetal lung fibroblasts (HFLs) to transforming growth factor-β1 (5 ng/mL) for 12 h, and examined the expression of SIK2, CRTCs and pCRTCs in fibroblasts by western-blot. To address the roles of SIK2 and CRTCs involved in the progression of pulmonary fibrosis, HFLs were treated with a small-molecule inhibitor ARN-3236 or by siRNA-mediated knockdown of SIK2 expression. Pulmonary fibrosis model was established with mice by exposing to bleomycin, and assessed by H&E and Masson's trichrome staining. COL1A and α-SMA distributions were detected in lung tissues by immunohistochemical staining.

Results: We discovered that SIK2 and phosphorylated-CRTC2 were expressed at a low basal level in normal lung tissues and quiescent fibroblasts, but increased in fibrotic lung tissues and activated fibroblasts. Inhibition of SIK2 by ARN-3236 prevented the fibroblasts differentiation and extracellular matrix expression in HFLs and attenuated bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inactivation of SIK2 resulted in the dephosphorylation and nuclear translocation of CRTC2. Within the nucleus, CRTC2 binds to CREB, promoting CREB-dependent anti-fibrotic actions.

Conclusion: In conclusion, our results elucidated a previously unexplored role of SIK2 in pulmonary fibrosis, and identified SIK2 as a new target for anti-fibrosis medicines.

Keywords

ARN-3236; CREB-regulated transcription co-activator 2 (CRTC2); Pulmonary fibrosis; Salt-inducible kinase 2 (SIK2); cAMP response element binding protein (CREB).

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