Transient Receptor Potential Vanilloid 4 Channel Regulates TGFβ1‐Mediated Fibroblast Differentiation And Airway Remodeling Through RAC/NADPH Oxidase 4 Axis

Abstract

Transient Receptor Potential Vanilloid 4 (TRPV4) is a stretch‐activated, mechano‐sensitive calcium channel. We have shown recently that TRPV4 regulates TGFβ1‐mediated fibroblast differentiation in vitro and D. farinae‐induced airway remodeling in vivo. Here, we present a unique finding that this regulation requires NADPH oxidase 4 (NOX4), a member of the NADPH oxidases. Our results reveal that TGFβ1 transcriptionally up‐regulated NOX4 gene expression and this expression was sensitive to TRPV4 inhibition. Further, TGFβ1‐induced fibrotic gene expression was inhibited by NOX4 antagonist (GKT137831), antioxidants and NOX4 siRNA. Interestingly, inhibition of Rac, a member of small family GTPases attenuated TGFβ1‐induced NOX‐4 upregulation and fibroblast differentiation, highlighting a novel TRPV4‐RAC‐NOX4 interaction. Importantly, TRPV4 KO mice which were protected from D. farinae‐induced asthma also exhibited lower levels of NOX4 gene expression, suggesting that TRPV4 promotes airway remodeling through NOX4. Our data unravels a unique role for TRPV4‐RAC‐NOX4 interaction in TGFβ1‐mediated fibroblast differentiation and lung remodeling.Support or Funding InformationThis work is supported by James Foght Assistant Professor support.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.