TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice

Title

TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice

Creator

Rahaman S O; Grove L M; Paruchuri S; Southern B D; Abraham S; Niese K A; Scheraga R G; Ghosh S; Thodeti C K; Zhang D X; Moran M M; Schilling W R; Tschumperlin D J; Olman M A

Publisher

Journal of Clinical Investigation

Date

2014
2014-12

Description

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-beta; 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-beta 1-dependent actions in a SMAD-independent manner, enhanced actomyosin remodeling, and increased nuclear translocation of the alpha-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.

Subject

activation; cation channel trpv4; contraction; disease; fibroblasts; gene-expression; induced lung injury; mechanisms; pathogenesis; Research & Experimental Medicine; tgf-beta

Identifier

Format

Journal Article

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Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Pages

5225-5238

Issue

12

Volume

124

Citation

Rahaman S O; Grove L M; Paruchuri S; Southern B D; Abraham S; Niese K A; Scheraga R G; Ghosh S; Thodeti C K; Zhang D X; Moran M M; Schilling W R; Tschumperlin D J; Olman M A, “TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice,” NEOMED Bibliography Database, accessed January 24, 2021, https://neomed.omeka.net/items/show/6839.

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