Highly Ca-permeable transient receptor potential vanilloid 6 contributes to the protection against colitis by regulating epithelial barrier function.

Abstract

Transient receptor potential vanilloid 6 (TRPV6) is a highly Ca-permeable cation channel predominantly expressed in the intestinal epithelium. It plays a crucial role in maintaining systemic calcium homeostasis by regulating Caabsorption in the intestine. However, its local physiological and pathophysiological roles in the intestine remain unexplored. The exact cause of inflammatory bowel disease is not fully understood; however, disruption of the intestinal epithelial barrier is a key pathogenic mechanism. In this study, we aimed to elucidate the role of TRPV6 in the pathogenesis of colitis. Experimental colitis was induced in TRPV6-deficient [knockout (KO)] and wild-type (WT) mice by administering 2% dextran sulfate sodium (DSS) solution in drinking water for 7 days. DSS treatment resulted in weight loss, diarrhea/bloody stool, histological colonic injury, and colon shortening. The systemic symptoms and colonic injury were significantly worse in TRPV6KO mice than in WT mice. DSS treatment increased tumor necrosis factor-α, interleukin-1β, interleukin-6 mRNA expressions, and myeloperoxidase activity, and these responses were significantly enhanced in TRPV6KO mice compared with WT mice. Under normal (no DSS-treated) conditions, TRPV6KO mice exhibited increased intestinal permeability compared with WT mice. No difference was observed in the number of goblet cells between WT and TRPV6KO mice; however, the expression of intercellular junction proteins, including E-cadherin, claudin-3, and occludin, was significantly suppressed in TRPV6KO mice compared with WT mice. These findings suggest that TRPV6 protects against DSS-induced colitis, potentially by regulating epithelial barrier function through intracellular junction protein expressions.This study is the first to reveal the local role of TRPV6 in the intestine. TRPV6KO exacerbated dextran sulfate sodium-induced colitis and increased intestinal permeability compared with wild-type mice. Furthermore, intercellular junction protein expression was lower in TRPV6KO mice. TRPV6 protects against colitis by maintaining epithelial barrier function by regulating intercellular junction protein expression. Thus, TRPV6 may be a novel therapeutic candidate for treating inflammatory bowel disease.