Mitigating endoplasmic reticulum stress with revaprazan ameliorates stress-related mucosal disease

Abstract

Background and Aim: The term stress-related mucosal disease (SRMD) represents conditions ranging from superficial mucosal damage to focal deep mucosal damage in the stomach, of which pathogenesis is deduced to be violent mucosal ischemia or excess oxidative stress, but not fully clarified yet. Under the hypothesis that mucosal cell apoptosis subsequent to endoplasmic reticulum (ER) stress might play a crucial role, we evaluated the efficacy and mechanism that novel acid pump antagonist (APA), revaprazan, alleviated water immersion restraint stress (WIRS) induced SRMD in rats. Methods: In order to define whether WIRS-induced SRMD is associated with ER stress, we checked the alteration in the expression of ER stress markers including GRP78, CHOP, XBP-1, BiP as well as apoptosis in WIRS-induced SRMD. The efficacy of revaprazan on either alleviating ER stress or attenuating SRMD was compared with proton pump inhibitor (PPI) and gastroprotectant. Results: Ten hours of WIRS induced a severe degree of SRMD, in which ER stress markers including CHOP, XBP1, and BiP were significantly overexpressed in the gastric tissues. However, these markers of ER stress were significantly decreased in the group pretreated with revaprazan compared to PPI or gastroprotectant, accompanied with a significant reduction in apoptotic index. In addition to ER stress, revaprazan imposed anti-inflammatory benefit to limit SRMD based on significant levels of inflammatory cell apoptosis. Conclusion: Endoplasmic reticulum stress accompanied with drastic apoptosis was implicated in the development of SRMD, but revaprazan could rescue the stomach from SRMD through alleviating ER stress in epithelial cells much better than either PPI or gastroprotectant.