Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation. Am J Physiol Cell Physiol 2017 May 01;312(5):C562-C572

Date

03/03/2017

Pubmed ID

28249987

Pubmed Central ID

PMC6105932

DOI

10.1152/ajpcell.00187.2016

Scopus ID

2-s2.0-85018753321   22 Citations

Abstract

Scleroderma is a multisystem fibroproliferative disease with no effective medical treatment. Myofibroblasts are critical to the fibrogenic tissue repair process in the skin and many internal organs. Emerging data support a role for both matrix stiffness, and transforming growth factor β1 (TGFβ1), in myofibroblast differentiation. Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel activated by both mechanical and biochemical stimuli. The objective of this study was to determine the role of TRPV4 in TGFβ1- and matrix stiffness-induced differentiation of dermal fibroblasts. We found that TRPV4 channels are expressed and functional in both human (HDF) and mouse (MDF) dermal fibroblasts. TRPV4 activity (agonist-induced Ca2+ influx) was induced by both matrix stiffness and TGFβ1 in dermal fibroblasts. TGFβ1 induced expression of TRPV4 proteins in a dose-dependent manner. Genetic ablation or pharmacological antagonism of TRPV4 channel abrogated Ca2+ influx and both TGFβ1-induced and matrix stiffness-induced myofibroblast differentiation as assessed by 1) α-smooth muscle actin expression/incorporation into stress fibers, 2) generation of polymerized actin, and 3) expression of collagen-1. We found that TRPV4 inhibition abrogated TGFβ1-induced activation of AKT but not of Smad2/3, suggesting that the mechanism by which profibrotic TGFβ1 signaling in dermal fibroblasts is modified by TRPV4 may be through non-Smad pathways. Altogether, these data identify a novel reciprocal functional link between TRPV4 activation and TGFβ1 signals regulating dermal myofibroblast differentiation. These findings suggest that therapeutic inhibition of TRPV4 activity may provide a targeted approach to the treatment of scleroderma.

Author List

Sharma S, Goswami R, Merth M, Cohen J, Lei KY, Zhang DX, Rahaman SO

Author

David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Differentiation
Cells, Cultured
Elastic Modulus
Extracellular Matrix
Gene Expression Regulation, Developmental
Humans
Ion Channel Gating
Mechanotransduction, Cellular
Mice
Mice, Inbred C57BL
Mice, Knockout
Myofibroblasts
Skin
Species Specificity
TRPV Cation Channels
Transforming Growth Factor beta1
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a