Paricalcitol alleviates intestinal ischemia-reperfusion injury via inhibition of the ATF4-CHOP pathway

Introduction Intestinal ischemia reperfusion (I/R) injury is a severe condition characterized by inflammation, oxidative stress, and compromised intestinal barrier function, which can lead to death. This study investigated the effects of paricalcitol, a synthetic vitamin D receptor (VDR) agonist, on intestinal I/R injury, focusing on the activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) signaling pathway and the modulation of endoplasmic reticulum stress (ERS). Methods This study consists of both in vivo and in vitro experiments. In vivo experiment, a mouse model of intestinal I/R injury was established by clamping the superior mesenteric artery, and followed by 24 or 72 h of reperfusion. 6-week-old male C57BL/6 J mice were randomly assigned to six groups: sham, I/R 24h, I/R 72 h, and their respective paricalcitol-treated counterparts. VDR knockout mice and wild-type mice were assigned to WT, VDR-KO, WT + I/R and VDR-KO + I/R groups. The paricalcitol-treated groups received oral gavage of paricalcitol (0.3 μg/kg) once daily for 5 days before I/R. In vitro , IEC-6 cells were incubated in a microaerophilic system (5% CO 2 , 1% O 2 , 94% N 2 ) for 6 h to induce hypoxia. The cells were then transferred to complete medium with or without paricalcitol (200 nM) and cultured under normoxic conditions for 24 h to establish the hypoxia/re-oxygenation (H/R) model and investigate the protective effects of paricalcitol on H/R-induced injury in cells. We further utilized VDR- and ATF4-silenced cells to examine how paricalcitol regulates the expression of VDR, ATF4, and CHOP. Results We demonstrated that protective paricalcitol treatment reduces ERS and apoptosis by activating VDR and inhibiting the ATF4-CHOP pathway, thereby alleviating intestinal I/R injury in vivo and H/R injury in vitro . Furthermore, experiments with VDR knockout mice demonstrated that the absence of VDR exacerbated I/R injury, underscoring the protective role of VDR in intestinal epithelial cells. Discussion These findings suggest that the protective effects of paricalcitol may offer a promising therapeutic strategy for managing intestinal I/R injury.