Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression.

Version 1 : Received: 1 February 2024 / Approved: 2 February 2024 / Online: 2 February 2024 (06:39:42 CET)

A peer-reviewed article of this Preprint also exists.

Nishiyama, K.; Kato, Y.; Nishimura, A.; Mi, X.; Nagata, R.; Mori, Y.; Azuma, Y.-T.; Nishida, M. Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression. Int. J. Mol. Sci. 2024, 25, 2401. Nishiyama, K.; Kato, Y.; Nishimura, A.; Mi, X.; Nagata, R.; Mori, Y.; Azuma, Y.-T.; Nishida, M. Pharmacological Activation of TRPC6 Channel Prevents Colitis Progression. Int. J. Mol. Sci. 2024, 25, 2401.

Abstract

Zn2+ has been implicated in the regulation of intestinal redox and microbial homeostasis, and we recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in mammalian cells. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in stress resistance of intestine. Expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using GEO database. Systemic TRPC3-knockout (KO) and TRPC6-KO mice were treated with dextran sulphate 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 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.

Keywords

Canonical transient receptor potential 6; Colitis; Stress resistance; Gut microbiota

Subject

Medicine and Pharmacology, Gastroenterology and Hepatology

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