Role of transient receptor potential vanilloid 4 activation in indomethacin-induced intestinal damage.

Abstract

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.

• Authors: Hidemoto Yamawaki, Hiroshi Mihara, Nobuhiro Suzuki, Hirofumi Nishizono, Kunitoshi Uchida, Shiro Watanabe, Makoto Tominaga, Toshiro Sugiyama
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 307 Issue 1 Pg. G33-40 (Jul 01 2014) ISSN: 1522-1547 [Electronic] United States
• PMID: 24789205 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 the American Physiological Society.

Chemical References

• TRPV Cation Channels
• TRPV4 protein, human
• Trpv4 protein, mouse
• Trpv4 protein, rat
• Arachidonic Acid
• Indomethacin

Topics

• Adult
• Aged
• Animals
• Arachidonic Acid (metabolism)
• Calcium Signaling
• Cell Line
• Disease Models, Animal
• Electric Impedance
• Humans
• Indomethacin
• Intestine, Small (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Peptic Ulcer (chemically induced, genetics, metabolism, pathology)
• Permeability
• RNA Interference
• Rats
• TRPV Cation Channels (antagonists & inhibitors, deficiency, drug effects, genetics, metabolism)
• Time Factors
• Transfection