Empagliflozin improves renal injury of diabetic nephropathy complicated with hyperuricemia through AMPK by promoting autophagy and inhibiting apoptosis

Objective: This study aimed to investigate how empagliflozin alleviates renal injury in diabetic nephropathy with hyperuricemia by activating AMPK and regulating Autophagy and Apoptosis.

Methods: This study incorporated clinical renal tissue samples, diabetic-hyperuricemic mouse models, and HK-2 tubular epithelial cells to investigate the effects of empagliflozin on renal injury. Diabetic nephropathy with hyperuricemia was modeled using streptozotocin and high-fat diet in mice, while HK-2 cells were treated with high glucose and uric acid in vitro. Empagliflozin was administered with or without AMPK inhibition to assess its regulatory role.

Results: In renal tissues and HK-2 cells under high-glucose and high-uric acid conditions, Empagliflozin treatment increased LC3 expression and AMPK phosphorylation, and decreased cleaved Caspase-3 levels. In diabetic-hyperuricemic mice, Empagliflozin also ameliorated fibrosis and reduced pathological damage. These effects were reversed upon co-treatment with Compound C, an AMPK Inhibitor, which suppressed Autophagy activation and restored apoptotic signaling. These results indicate that Empagliflozin exerts reno-protective effects by activating AMPK to promote Autophagy and inhibit Apoptosis, and that AMPK plays a central mechanistic role in mediating these effects.

Conclusion: Empagliflozin alleviates renal injury in diabetic nephropathy with hyperuricemia by activating AMPK, promoting Autophagy, and inhibiting Apoptosis, suggesting its potential therapeutic value in managing this complication.

AMPK; Apoptosis; Autophagy; Diabetic nephropathy; Empagliflozin; Hyperuricemia.