TRPV4 channels regulates matrix stiffness and TGFβ1‐induced epithelial‐mesenchymal transition

Abstract

Epithelial‐mesenchymal transition (EMT) has important functions in cellular processes including development, wound healing, oncogenesis, and fibrosis. Emerging data support a role for both a mechanical signal, and a biochemical signal, e.g., transforming growth factor β1 (TGFβ1), in EMT. Here, we report evidence showing that transient receptor potential vanilloid 4 (TRPV4), calcium‐permeable channel and member of TRP superfamily, is the likely mediator of EMT in response to both TGFβ1 and matrix stiffness. Specifically, we found that: i) genetic ablation of TRPV4 blocked TGFβ1‐induced EMT in normal mouse primary epidermal keratinocytes (NMEKs) as determined by changes in morphology and alterations of expression of EMT markers including E‐cadherin (ECAD), N‐cadherin (NCAD), and α‐smooth muscle actin (α‐SMA), and ii) 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. We found an increased co‐localization of TRPV4 with NCAD, and decreased co‐localization of TRPV4 with epithelial marker ECAD in skin tissues of bleomycin‐treated wild‐type mice compared to saline controls. Mechanistically, we found that: i) 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, ii) TRPV4 deletion inhibited both matrix stiffness‐ and TGFβ1‐induced expression of YAP/TAZ proteins, and iii) 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, and thus suggest that therapeutic targeting of TRPV4 may provide a selective approach to ameliorate the development of skin fibrosis and oncogenesis.Support or Funding InformationAHA (13SDG17310007), Startup grant from University of Maryland, NIH (1R01EB024556‐01), and NSF (CMMI‐1662776) grants to SOR.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.