TRPV4 regulates matrix stiffness and TGFβ1-induced epithelial-mesenchymal transition. J Cell Mol Med 2019 Feb;23(2):761-774
Date
11/20/2018Pubmed ID
30450767Pubmed Central ID
PMC6349341DOI
10.1111/jcmm.13972Scopus ID
2-s2.0-85056765656 (requires institutional sign-in at Scopus site) 78 CitationsAbstract
Substrate stiffness (or rigidity) of the extracellular matrix has important functions in numerous pathophysiological processes including fibrosis. Emerging data support a role for both a mechanical signal, for example, matrix stiffness, and a biochemical signal, for example, transforming growth factor β1 (TGFβ1), in epithelial-mesenchymal transition (EMT), a process critically involved in fibrosis. Here, we report evidence showing that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive channel, is the likely mediator of EMT in response to both TGFβ1 and matrix stiffness. Specifically, we found that: (a) genetic ablation or pharmacological inhibition of TRPV4 blocked matrix stiffness and TGFβ1-induced EMT in normal mouse primary epidermal keratinocytes (NMEKs) as determined by changes in morphology, adhesion, migration and alterations of expression of EMT markers including E-cadherin, N-cadherin (NCAD) and α-smooth muscle actin (α-SMA), and (b) TRPV4 deficiency prevented matrix stiffness-induced EMT in NMEKs over a pathophysiological range. Intriguingly, TRPV4 deletion in mice suppressed expression of mesenchymal markers, NCAD and α-SMA, in a bleomycin-induced murine skin fibrosis model. Mechanistically, we found that: (a) TRPV4 was essential for the nuclear translocation of YAP/TAZ (yes-associated protein/transcriptional coactivator with PDZ-binding motif) in response to matrix stiffness and TGFβ1, (b) TRPV4 deletion inhibited both matrix stiffness- and TGFβ1-induced expression of YAP/TAZ proteins and (c) TRPV4 deletion abrogated both matrix stiffness- and TGFβ1-induced activation of AKT, but not Smad2/3, suggesting a mechanism by which TRPV4 activity regulates EMT in NMEKs. Altogether, these data identify a novel role for TRPV4 in regulating EMT.
Author List
Sharma S, Goswami R, Zhang DX, Rahaman SOAuthor
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ActinsAdaptor Proteins, Signal Transducing
Animals
Bleomycin
Cadherins
Cell Adhesion
Cell Cycle Proteins
Cell Movement
Epidermis
Epithelial-Mesenchymal Transition
Extracellular Matrix
Fibrosis
Gene Expression Regulation
Humans
Keratinocytes
Mechanotransduction, Cellular
Mice
Primary Cell Culture
Proto-Oncogene Proteins c-akt
Smad2 Protein
Smad3 Protein
TRPV Cation Channels
Trans-Activators
Transforming Growth Factor beta1
