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Objective <p>This study aimed to investigate how empagliflozin alleviates renal injury in diabetic nephropathy with hyperuricemia by activating AMPK and regulating autophagy and apoptosis.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p> Graphical Abstract <p>This study illustrates the mechanism by which empagliflozin alleviates renal tubular injury in diabetic nephropathy with hyperuricemia. Empagliflozin activates AMPK, which promotes the expression of LC3-II/I to enhance autophagy, reduces cleaved caspase-3 to inhibit apoptosis, and suppresses URAT1 to lower uric acid levels. These effects together protect renal tubular cells from injury under diabetic and hyperuricemic conditions.</p> <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Zhiqin Zhang,
  • Yanmei Xu,
  • Chuanwen Xu,
  • Qi Gao,
  • Xiaoyan Wu,
  • Ting Wu

摘要

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.

Graphical Abstract

This study illustrates the mechanism by which empagliflozin alleviates renal tubular injury in diabetic nephropathy with hyperuricemia. Empagliflozin activates AMPK, which promotes the expression of LC3-II/I to enhance autophagy, reduces cleaved caspase-3 to inhibit apoptosis, and suppresses URAT1 to lower uric acid levels. These effects together protect renal tubular cells from injury under diabetic and hyperuricemic conditions.