Long Noncoding RNA FENDRR Exhibits Antifibrotic Activity in Pulmonary Fibrosis.

Abstract

Abnormal activation of lung fibroblasts contributes to the initiation and progression of idiopathic pulmonary fibrosis (IPF). The objective of the present study was to investigate the role of fetal-lethal noncoding developmental regulatory RNA (FENDRR) in the activation of lung fibroblasts. Dysregulated long noncoding RNAs in IPF lungs were identified by next-generation sequencing analysis from the two online datasets. FENDRR expression in lung tissues from patients with IPF and mice with bleomycin-induced pulmonary fibrosis was determined by quantitative real-time PCR. IRP1 (iron-responsive element-binding protein 1), a protein partner of FENDRR, was identified by RNA pulldown-coupled mass spectrometric analysis and confirmed by RNA immunoprecipitation. The interaction region between FENDRR and IRP1 was determined by cross-linking immunoprecipitation. The in vivo role of FENDRR in pulmonary fibrosis was studied using adenovirus-mediated gene transfer in mice. The expression of FENDRR was downregulated in fibrotic human and mouse lungs as well as in primary lung fibroblasts isolated from bleomycin-treated mice. TGF-β1 (transforming growth factor-β1)-SMAD3 signaling inhibited FENDRR expression in lung fibroblasts. FENDRR was preferentially localized in the cytoplasm of adult lung fibroblasts and bound IRP1, suggesting its role in iron metabolism. FENDRR reduced pulmonary fibrosis by inhibiting fibroblast activation by reducing iron concentration and acting as a competing endogenous RNA of the profibrotic microRNA-214. Adenovirus-mediated FENDRR gene transfer in the mouse lung attenuated bleomycin-induced lung fibrosis and improved lung function. Our data suggest that FENDRR is an antifibrotic long noncoding RNA and a potential therapeutic target for pulmonary fibrosis.

• Authors: Chaoqun Huang, Yurong Liang, Xiangming Zeng, Xiaoyun Yang, Dao Xu, Xuxu Gou, Roshini Sathiaseelan, Lakmini Kumari Senavirathna, Pengcheng Wang, Lin Liu
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 62 Issue 4 Pg. 440-453 (04 2020) ISSN: 1535-4989 [Electronic] United States
• PMID: 31697569 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• MicroRNAs
• RNA, Long Noncoding
• Smad3 Protein
• Transforming Growth Factor beta1
• Bleomycin

Topics

• Animals
• Bleomycin (pharmacology)
• Cells, Cultured
• Down-Regulation (drug effects, genetics)
• Fibroblasts (drug effects, metabolism)
• Humans
• Idiopathic Pulmonary Fibrosis (genetics)
• Lung (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• MicroRNAs (genetics)
• RNA, Long Noncoding (genetics)
• Signal Transduction (drug effects, genetics)
• Smad3 Protein (genetics)
• Transforming Growth Factor beta1 (genetics)