Role of transient receptor potential vanilloid 4 activation in indomethacin-induced intestinal damage.
Gastrointestinal ulcers and bleeding are serious complications of nonsteroidal anti-inflammatory drug (NSAID) use. Although administration of antibiotics and Toll-like receptor 4 knockdown mitigate NSAID-induced enteropathy, the molecular mechanism of these effects is poorly understood. Intestinal hyperpermeability is speculated to trigger the initial damage due to NSAID use. Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel expressed throughout the gastrointestinal tract epithelium that is activated by temperature, extension, and chemicals such as 5,6-epoxyeicosatrienoic acid (5,6-EET). The aim of this study was to investigate the possible role of TRPV4 in NSAID-induced intestinal damage. TRPV4 mRNA and protein expression was confirmed by RT-PCR and immunochemistry, respectively, in mouse and human tissues while TRPV4 channel activity of the intestinal cell line IEC-6 was assessed by Ca(2+)-imaging analysis. TRPV4 activators or the NSAID indomethacin significantly decreased transepithelial resistance (TER) in IEC-6 cells, and indomethacin-induced TER decreases were inhibited by specific TRPV4 inhibitors or small-interfering RNA TRPV4 knockdown, as well as by the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, which decreased 5,6-EET levels. In TRPV4 knockout mice, indomethacin-induced intestinal damage was significantly reduced compared with WT mice. Taken together, these results show that TRPV4 activation in the intestinal epithelium caused epithelial hyperpermeability in response to NSAID-induced arachidonic acid metabolites and contributed to NSAID-induced intestinal damage. Thus, TRPV4 could be a promising new therapeutic target for the prevention of NSAID-induced intestinal damage.
Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan;
Hidemoto
H
Yamawaki
Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan;
Hiroshi
H
Mihara
Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan;
Nobuhiro
N
Suzuki
Division of Animal Experimental Laboratory, Life Science Research Center, University of Toyama, Toyama, Japan;
Hirofumi
H
Nishizono
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Japan; and.
Kunitoshi
K
Uchida
Division of Nutritional Biochemistry, Institute of Natural Medicines, University of Toyama, Japan.
Shiro
S
Watanabe
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Japan; and.
Makoto
M
Tominaga
Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; tsugi@med.u-toyama.ac.jp.
Toshiro
T
Sugiyama
D000328:Adult; D000368:Aged; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D020013:Calcium Signaling; D002460:Cell Line; D004195:Disease Models, Animal; D017097:Electric Impedance; D006801:Humans; D007213:Indomethacin; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010437:Peptic Ulcer / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010539:Permeability; D034622:RNA Interference; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse; C486577:Trpv4 protein, rat; D016718:Arachidonic Acid; D007213:Indomethacin
intestine; nonsteroidal anti-inflammatory drugs