Long Noncoding RNA FENDRR Exhibits Antifibrotic Activity in Pulmonary Fibrosis
Long Noncoding RNA FENDRR Exhibits Antifibrotic Activity in Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2018-0293oc
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发表时间：
2020-04-01
影响因子：
6.4
通讯作者：
Liu, Lin
中科院分区：
文献类型：
--
作者：
Huang, Chaoqun;Liang, Yurong;Liu, Lin
肺成纤维细胞的异常激活参与了特发性肺纤维化(IPF)的发生发展。本研究的目的是探讨胎儿致死性非编码发育调节RNA(Fendrr)在肺成纤维细胞激活中的作用。通过来自两个在线数据集的下一代测序分析，在IPF肺中识别出异常调节的长非编码RNA。用实时定量聚合酶链式反应检测IPF患者和博莱霉素性肺纤维化小鼠肺组织中FendrR的表达。通过RNA下拉耦合质谱分析和RNA免疫沉淀鉴定了Fendr1的铁反应元件结合蛋白1(Iron-Response Element-Binding Protein 1)。用交联型免疫沉淀法测定Fendrr与Irp1的相互作用区域。用腺病毒介导的基因转移方法研究Fendrr在小鼠肺纤维化中的体内作用。Fendrr在纤维化的人和小鼠肺以及博莱霉素处理的小鼠的原代肺成纤维细胞中的表达下调。转化生长因子-β1-Smad3信号通路抑制肺成纤维细胞Fendrr的表达。FendrR优先定位于成人肺成纤维细胞的胞浆中，并与Irp1结合，提示其在铁代谢中的作用。Fendrr通过降低铁浓度来抑制成纤维细胞的激活，并充当促纤维化microRNA-214的竞争内源RNA，从而减少了肺纤维化。腺病毒介导的小鼠肺内Fendrr基因转移减轻博莱霉素诱导的肺纤维化并改善肺功能。我们的数据表明，Fendrr是一种抗纤维化的长非编码RNA，是治疗肺纤维化的潜在靶点。
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-beta 1 (transforming growth factor-beta 1)-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.