Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression

Author:

Nishiyama Kazuhiro12,Kato Yuri1ORCID,Nishimura Akiyuki345ORCID,Mi Xinya1,Nagata Ryu6,Mori Yasuo7,Azuma Yasu-Taka2ORCID,Nishida Motohiro13458ORCID

Affiliation:

1. Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan

2. Laboratory of Prophylactic Pharmacology, Osaka Metropolitan University Graduate School of Veterinary Science, Osaka 598-8531, Japan

3. National Institute for Physiological Sciences (NIPS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan

4. Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, Okazaki 444-8787, Japan

5. SOKENDAI (Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies), Okazaki 444-8787, Japan

6. Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan

7. Graduate School of Engineering, Kyoto University, Kyoto 615-8530, Japan

8. Department of Physiology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan

Abstract

We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis.

Funder

JST CREST

JSPS KAKENHI

Ministry of Education, Culture, Sports, Science and Technology of Japan

Naito and Takeda Science Foundation

Research Support Project for Life Science and Drug Discovery (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED

Publisher

MDPI AG

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