Cited by 90Ion Channels and ReceptorsSystemic Sclerosis and Related DiseasesTGF-β signaling in diseases

TRPV4 ion channel is a novel regulator of dermal myofibroblast differentiation

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Sharma, Shweta, Goswami, Rishov, Merth, Michael, Cohen, Jonathan, Lei, Kai Y., Zhang, David X., Rahaman, Shaik O.·2017·American Journal of Physiology-Cell Physiology

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.

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Crossref · 10.1152/ajpcell.00187.2016

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  • TRPV4 can activate TGF-β1/AKT signal and enhance differentiation of dermal myofibroblasts and increase in collagen content induced by TGF-β1.

    “Furthermore, TRPV4 can activate the TGF-β1/AKT signal and enhance the differentiation of dermal myofibroblasts and the increase in collagen content induced by TGF-β1 [95] (Figure 1).”

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Authors
Sharma, S., Goswami, R., Merth, M., Cohen, J., Lei, K. Y., Zhang, D. X., & Rahaman, S. O.
Affiliations
  • University of Maryland, College Park (US)
  • Medical College of Wisconsin (US)
Corresponding author
Rahaman, Shaik O.
Venue
American Journal of Physiology-Cell Physiology
Published
2017-05-01
Volume
312
Issue
5
Pages
C562-C572
ISSN
  • 0363-6143 (ISSN-L)
  • 1522-1563
OpenAlex
W2592906727
Cited by
90
References
56
Citations by year
2026: 10 · 2025: 19 · 2024: 6 · 2023: 4 · 2022: 11 · 2021: 9 · 2020: 14 · 2019: 10 · 2018: 5 · 2017: 2
FWCI
5.30
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Cell Physiology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
American Heart Association (AHA) (13SDG17310007)
Topics
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Systemic Sclerosis and Related Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
TRPV4, myofibroblast differentiation, systemic sclerosis, TGF-β1 signaling, extracellular matrix stiffness, mechanosensitive ion channels, calcium influx, dermal fibroblasts, Akt signaling, collagen-1, alpha-smooth muscle actin, actin polymerization, skin fibrosis
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Extracellular Matrix, Humans, Mice, Inbred C57BL, Skin, Species Specificity, Ion Channel Gating, Mice, Knockout, Gene Expression Regulation, Developmental, Mechanotransduction, Cellular, TRPV Cation Channels, Mice, Transforming Growth Factor beta1, Elastic Modulus, Myofibroblasts

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