Pharmacological Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Alleviates Carbon Tetrachloride-Induced Liver Fibrosis in Mice

Abstract

Background: Transient receptor potential vanilloid 4 (TRPV4) is a member of the TRP channel family and is involved in diverse physiological and pathological processes. Accumulating evidence from in vitro studies indicates that TRPV4 has a potential role in liver fibrosis, but its precise role in the pathophysiological development of this condition is unclear. Exogenous interventions and endogenous reactions should be considered. Methods:This study used a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis to investigate the effects of intraperitoneal injection of the novel TRPV4 channel selective agonist GSK1016790A (GSK) and antagonist HC-067047 (HC). Results:As compared with the CCl4 group, collagen fiber deposition and alpha-smooth muscle actin (α-SMA) levels were markedly higher and hepatic lobule disorganization was worse in the CCl4+GSK group, while collagen fiber deposition was significantly lower and hepatic lobule disorganization was less severe in the CCl4+HC group. Conclusions:The present findings suggest that activation of TRPV4 channels worsens liver fibrosis and that inhibition of TRPV4 channels may alleviate liver fibrosis in vivo.

Expression and functions of transient receptor potential channels in liver diseases

“…Blockade of TRPV4 using ruthenium red or TRPV4-siRNA inhibits the proliferation of HSC-T6 cells and decreases myofibroblast markers α -smooth muscle actin ( α -SMA) and COL1A1 79 . These results are in line with pharmacological inhibition of TRPV4 in a mouse model of CCl 4 -induced liver fibrosis, where collagen fiber deposition and α -SMA levels are markedly diminished meanwhile the hepatic lobule disorganization is noticeably alleviated 80 .…”

Deletion of TRPC3 or TRPC6 Fails to Attenuate the Formation of Inflammation and Fibrosis in Non-alcoholic Steatohepatitis

“…Animals All procedures used in this study were approved by the ethic committees at the Animal Care and Use Committee, Kyushu University. We produced C57BL/6 strain mice with systemic knockout (KO) of TRPC3 or TRPC6 (8-11 weeks old, male) by backcrossing 129Sv strain TRPC-deficient mice kindly provided by Dr. Birnbaumer (NIEHS, U.S.A.) 7,12) onto C57BL/6 backgoround mice. Animals were maintained under a 12 h/12 h light/dark cycle.…”

“…6) In TRPC3-deficient mice, cardiac fibrosis is diminished in response to pressure overload. 7) TRPC3/C6 deletion ameliorates cardiac hypertrophy and fibrosis induced by pressure overload. 8) Additionally, selective inhibition of TRPC6 improves left heart function and fibrosis in mice that are subjected to sustained pressure overload.…”

Transient receptor potential vanilloid (TRPV) channels: Basal properties and physiological potential

“…In addition, in NOD/ ShiJic-scid mouse xenograft models, HC-067047 administration suppressed tumor growth and induced apoptosis (Fang et al 2018). Activation of the TRPV4 channel exacerbated liver fibrosis in a mouse model of carbon tetrachlorideinduced liver fibrosis, but HC-067047 treatment ameliorated the fibrosis (Fu et al 2019).…”