Dapagliflozin ameliorates high glucose-induced peritoneal fibrosis through downregulation of ENKUR/PI3K/AKT signaling pathway

Dapagliflozin (DAPA), an SGLT-2 inhibitor, shows peritoneal protection and can alleviate high glucose-induced peritoneal fibrosis. Yet, its precise molecular mechanism is unknown. This study aims to explore DAPA's protective effect on the peritoneum and its underlying mechanism. In vitro, human peritoneal mesothelial cells (HPMCs) were isolated from peritoneal dialysate and cultured. HMrSV5 cells were stimulated with 2.5% D-Glucose (high glucose, HG) for 48 h, then cultured in D-glucose DMEM medium with or without DAPA. To assess SGLT2i-induced ENKUR down-regulation, HMrSV5 cells were treated with DAPA for 24 h while overexpressing ENKUR. In vivo, six-week-old male Sprague-Dawley rats were treated with high-glucose dialysate via an intraperitoneal catheter, with or without addition of DAPA. Changes in SGLT2, ENKUR, PI3K/AKT pathways, and EMT markers were evaluated in HPMCs and the rat model. As dialysis duration increases the morphology of the cells transitioned from a cobblestone appearance to a spindle shape. Immunofluorescence analysis confirmed the mesothelial cell origin and revealed an upregulation of ENKUR and the PI3K/AKT signaling pathway, which are associated with the occurrence of EMT. DAPA was found to decrease the expression of ENKUR and inhibit the activation of the PI3K/AKT pathway induced by high glucose in HMrSV5 cells. In rats subjected to PD, we observed a reduction in ultrafiltration capacity, an increase in peritoneal thickness, and elevated levels of SGLT2, ENKUR, PI3K/AKT and EMT markers. Notably, these alterations were mitigated by intragastric administration of DAPA. DAPA effectively ameliorates high glucose-induced peritoneal fibrosis through downregulation of ENKUR/PI3K/AKT signaling pathway.