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Am J Physiol Lung Cell Mol Physiol. 2018 Oct 1;315(4):L563-L575. doi: 10.1152/ajplung.00434.2017. Epub 2018 Jun 28.

Inhibition of lncRNA PFRL prevents pulmonary fibrosis by disrupting the miR-26a/smad2 loop.

Jiang H1,2, Chen Y3, Yu T1,2, Zhao X1,2, Shan H1,2, Sun J1,2, Zhang L1,2, Li X1, Shan H1,2, Liang H1,2.

Author information

1
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University , Harbin , People's Republic of China.
2
Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University , Harbin , People's Republic of China.
3
Department of Pathology, the Second Affiliated Hospital, Harbin Medical University , Harbin , People's Republic of China.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with increasing mortality and poor prognosis. The current understanding of the role of long noncoding RNAs (lncRNAs) in IPF remains limited. In the present study, we identified a lncRNA NONMMUT022554, designated pulmonary fibrosis-regulatory lncRNA (PFRL), with unknown functions and found that its levels were increased in fibrotic lung tissues of mice and pulmonary fibroblasts exposed to transforming growth factor (TGF)-β1. Furthermore, we found that enforced expression of PFRL induced fibroblast activation and collagen deposition, which could be mitigated by the overexpression of microRNA (miR)-26a. By contrast, the inhibition of PFRL could markedly alleviate the TGF-β1-induced upregulation of fibrotic markers and attenuate fibroblast proliferation and differentiation by regulating miR-26a. Meanwhile, our study confirmed that PFRL inhibited the expression and activity of miR-26a, which has been identified as an antifibrotic miRNA in our previous study. Interestingly, our molecular study further confirmed that Smad2 transcriptionally inhibits the expression of miR-26a and that the miR-26a/Smad2 feedback loop mediates the profibrotic effects of PFRL in lung fibrosis. More importantly, knockdown of PFRL ablated bleomycin-induced pulmonary fibrosis in vivo. Taken together, our findings indicate that lncRNA PFRL contributes to the progression of lung fibrosis by modulating the reciprocal repression between miR-26a and Smad2 and that this lncRNA may be a therapeutic target for IPF.

PMID:
29952219
DOI:
10.1152/ajplung.00434.2017

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