Canagliflozin inhibits p38MAPK signaling to protect tubular epithelial cell against pyroptosis in sepsis-induced acute kidney injury.

Abstract

This paper aimed to investigate the impacts and mechanisms of canagliflozin (CANA) in sepsis-induced acute kidney injury (SAKI). SAKI models were established using HK2 cells treated with lipopolysaccharide (LPS) and mice received cecum ligation puncture (CLP) surgery. The pathological examination was applied to evaluate mouse kidney damage. Inflammatory cytokines were evaluated using ELISA and RT-qPCR assay. Flow cytometry and TUNEL staining were employed to check cell apoptosis. The expression of apoptosis-, inflammation-, pyroptosis-, and pathway-related proteins were assessed via western blot. In CLP-induced mouse SAKI model, CANA attenuated renal pathological injury, inflammation response, pyroptosis and inhibited the p38MAPK pathway, as evidenced by the decrease of serum Scr and BUN levels, cell apoptosis, IL-1β and IL-18 levels, as well as GSDMD-N, cleaved caspase-1, and p38MAPK expression. In HK2 cells treated with LPS, inflammation response, pyroptosis, and the p38MAPK pathway were inhibited by CANA. Moreover, overexpression of p38MAPK reversed CANAs' effects on apoptosis, inflammation response, and pyroptosis in HK2 cells. In SAKI, CANA inhibited the p38MAPK pathway, thereby reducing cell apoptosis, inflammation response, and pyroptosis, which ultimately alleviating disease progression.