Objective:To investigate the efficacy and mechanism of canagliflozin (Cana) in the treatment of high glucose-induced human podocyte (HPC) injury.Methods:The HPCs were divided into 5 groups: normal glucose group (NG group), mannitol group (MA group), high glucose group (HG group), Cana low dose (0.3 μmol/L) group and Cana high dose (1.0 μmol/L) group. Western blotting was used to examine the protein expressions of membrane-associated guanylate kinase inverted-2 (MAGI2), podocyte-associated protein nephrin, sodium-glucose transporter 2 (SGLT2), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis- associated speck-like protein containing a CARD (ASC), and cleaved-caspase1 in podocytes. Phalloidin staining of F-actin in podocytes was used to observe cytoskeletal injury. Intracellular reactive oxygen species (ROS) level of HPC was detected by the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) probe. Levels of interleukin (IL)-18 and IL-1β in culture medium of podocytes were detected by enzyme-linked immunosorbent assay (ELISA).Results:(1) Compared with the NG group, the protein expressions of MAGI2 and nephrin decreased (both P<0.01), the protein expression of SGLT2 increased ( P<0.01), the changes of cell morphology and cytoskeleton remodeling were obvious, intracellular ROS level increased ( P<0.01), while NLRP3, ASC and cleaved-caspase1 protein expressions decreased in the HG group (all P<0.01). The results of ELISA showed that IL-18 and IL-1β concentrations were higher in the HG group (both P<0.05). (2) Compared with the HG group, in the Cana groups, MAGI2 and nephrin expressions up-regulated (both P<0.01), the changes of cell morphology and cytoskeleton remodeling were alleviated. Meanwhile the Cana groups showed decreased SGLT2 expression ( P<0.05), lower ROS level, down- regulated NLRP3, ASC, cleaved-caspase1 expressions (all P<0.01), and decreased concentrations of IL-18 and IL-1β in culture medium of podocytes (both P<0.05). Conclusion:Cana can improve high glucose-induced injury and inflammation in human podocyte, possibly due to the repression of the ROS/NLRP3 signaling pathway.