title: miR-9-5p suppresses pro-fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2.
abstract: Uncontrolled extracellular matrix (ECM) production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Reactive oxygen species (ROS) generation is involved in the pathogenesis of IPF. Transforming growth factor-β1 (TGF-β1) stimulates the production of NADPH oxidase 4 (NOX4)-dependent ROS, promoting lung fibrosis (LF). Dysregulation of microRNAs (miRNAs) has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. miR-9-5p was selected as the best candidate and we demonstrate its inhibitory effect on TGF-β receptor type II (TGFBR2) and NOX4 expression. Increased expression of miR-9-5p abrogates TGF-β1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, miR-9-5p dramatically reduces fibrogenesis and inhibition of miR-9-5p and prevents its anti-fibrotic effect both in vitro and in vivo. In lung specimens from patients with IPF, high levels of miR-9-5p are found. In omentum-derived mesothelial cells (MCs) from patients subjected to peritoneal dialysis (PD), miR-9-5p also inhibits mesothelial to myofibroblast transformation. We propose that TGF-β1 induces miR-9-5p expression as a self-limiting homeostatic response.
authors: Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors: Marta
authors: M
authors: Fierro-Fernández
authors: Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors: Óscar
authors: Ó
authors: Busnadiego
authors: Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors: Pilar
authors: P
authors: Sandoval
authors: Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors: Cristina
authors: C
authors: Espinosa-Díez
authors: Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors: Eva
authors: E
authors: Blanco-Ruiz
authors: Department of Pathology, Hospital Universitario "Ramón y Cajal", IRYCIS, Madrid, Spain.
authors: Macarena
authors: M
authors: Rodríguez
authors: Department of Pathology, Hospital Universitario "Ramón y Cajal", IRYCIS, Madrid, Spain.
authors: Héctor
authors: H
authors: Pian
authors: Genomic Facility, Parque Científico de Madrid, Madrid, Spain.
authors: Ricardo
authors: R
authors: Ramos
authors: Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors: Manuel
authors: M
authors: López-Cabrera
authors: Department of Pathology, Hospital Universitario "Ramón y Cajal", IRYCIS, Madrid, Spain.
authors: Maria Laura
authors: ML
authors: García-Bermejo
authors: Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain slamas@cbm.csic.es.
authors: Santiago
authors: S
authors: Lamas
mesh_terms: D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D005355:Fibrosis / Q000235:genetics*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000302:isolation & purification; D058628:Myofibroblasts / Q000502:physiology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000494:pharmacology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D017382:Reactive Oxygen Species; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: TGF‐β signaling; fibrosis; miRNAs; myofibroblast; oxidative stress