title: TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice.
abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disorder with no effective medical treatments available. The generation of myofibroblasts, which are critical for fibrogenesis, requires both a mechanical signal and activated TGF-β; however, it is not clear how fibroblasts sense and transmit the mechanical signal(s) that promote differentiation into myofibroblasts. As transient receptor potential vanilloid 4 (TRPV4) channels are activated in response to changes in plasma membrane stretch/matrix stiffness, we investigated whether TRPV4 contributes to generation of myofibroblasts and/or experimental lung fibrosis. We determined that TRPV4 activity is upregulated in lung fibroblasts derived from patients with IPF. Moreover, TRPV4-deficient mice were protected from fibrosis. Furthermore, genetic ablation or pharmacological inhibition of TRPV4 function abrogated myofibroblast differentiation, which was restored by TRPV4 reintroduction. TRPV4 channel activity was elevated when cells were plated on matrices of increasing stiffness or on fibrotic lung tissue, and matrix stiffness-dependent myofibroblast differentiation was reduced in response to TRVP4 inhibition. TRPV4 activity modulated TGF-β1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the α-SMA transcription coactivator (MRTF-A). Together, these data indicate that TRPV4 activity mediates pulmonary fibrogenesis and suggest that manipulation of TRPV4 channel activity has potential as a therapeutic approach for fibrotic diseases.
authors.forename: Shaik O
authors.initials: SO
authors.lastname: Rahaman
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Grove
authors.forename: Sailaja
authors.initials: S
authors.lastname: Paruchuri
authors.forename: Brian D
authors.initials: BD
authors.lastname: Southern
authors.forename: Susamma
authors.initials: S
authors.lastname: Abraham
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Niese
authors.forename: Rachel G
authors.initials: RG
authors.lastname: Scheraga
authors.forename: Sudakshina
authors.initials: S
authors.lastname: Ghosh
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
authors.forename: David X
authors.initials: DX
authors.lastname: Zhang
authors.forename: Magdalene M
authors.initials: MM
authors.lastname: Moran
authors.forename: William P
authors.initials: WP
authors.lastname: Schilling
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Tschumperlin
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Olman
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D002454:Cell Differentiation; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D058628:Myofibroblasts / Q000378:metabolism* / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050916:TRPV Cation Channels / Q000096:biosynthesis* / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; C511173:Mrtfa protein, mouse; D050916:TRPV Cation Channels; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; C486576:Trpv4 protein, mouse; D001761:Bleomycin