Slc26a9 guards gastric mucosa against portal hypertension by reducing ER stress-induced apoptosis

Slc26a9 is a member of the Slc26a family that is highly expressed in the stomach and is a key regulator for maintaining gastric mucosal homeostasis. Slc26a9 deletion in mice impairs the gastric mucosal barrier. However, the role of Slc26a9 in PHG has never been investigated.

Slc26a9 expression was analyzed in human PHG and control gastric tissues. A PVL-induced PHG model was established in Slc26a9^fl/fl and parietal cell-specific Slc26a9 knockout mice to evaluate mucosal injury, ER stress, and apoptosis. Adenoviral overexpression in vivo and gene silencing in GES-1 cells were used to explore the underlying mechanisms.

In this study, the Human PHG samples showed both significantly reduced Slc26a9 mRNA and protein expression when compared to healthy controls. Parietal cell-specific Slc26a9 gene deletion aggravates gastric mucosal injury, gastric mucosal epithelial apoptosis, mitochondria apoptotic, and ER stress in PHG. Restoration of Slc26a9 expression in the gastric mucosa of mice using an adenovirus overexpressing Slc26a9 reversed the aggravated endoplasmic reticulum stress, mitochondrial apoptosis, epithelial apoptosis, and gastric mucosal injury caused by Slc26a9 deficiency. In addition, downregulation of Slc26a9 expression induced apoptosis in GES-1 cells by activating the endoplasmic reticulum stress-mitochondrial apoptosis pathway. Mechanistically, Slc26a9 may inhibit endoplasmic reticulum stress by interacting with valosin-containing protein (VCP).

Slc26a9 protects the mucosal defense barrier against PHG by attenuating ER stress-mediated mitochondria-dependent apoptotic signaling. Slc26a9 may be a novel therapeutic target for PHG.