Histology and histopathology · 2026
Henagliflozin promotes mitophagy in renal tubular cells by activating AMPK/ULK1 to alleviate the progression of diabetic kidney disease.
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Wang Yanqiu, Chen Ziang, Zhang Yali, Shao Chen, Zha Xiujing, Wang Diwen
Аннотация
BACKGROUND: Diabetic Kidney Disease (DKD) is a leading cause of end-stage kidney disease. As an inhibitor of sodium-glucose cotransporter 2 (SGLT2), Henagliflozin (Hen) has been shown to have significant renoprotection effects. However, the underlying mechanisms remain to be elucidated.
METHODS: In clinical studies, patients with DKD were treated with Hen and Metformin (MET) for three months to examine their protection against renal injury. In vivo, C57BL/6 mice were subject to streptozotocin and a high-fat diet to induce DKD, followed by Hen (50 mg/kg/d) and MET (200 mg/kg/d) for eight weeks. In vitro, HK2 cells were exposed to high glucose (HG) (30 mM) and Hen (10 μM) for 24h. In rescue experiments, HK2 cells were transfected with sh-AMPK plasmids and subsequently treated with HG and Hen for 24h.
RESULTS: Renal injury and the inhibition of autophagy were both observed in patients with DKD and DKD mice. Consistent with these observations, HG-treated HK2 cells exhibited reduced cell viability and impaired autophagy activity. Hen treatment significantly ameliorated renal injury in DKD mice and enhanced cell viability in HG-treated HK2 cells. Furthermore, Hen exerts its protective effects by activating AMPK/ULK1-mediated mitophagy. Notably, AMPK downregulation effectively inhibited the activation of mitophagy induced by Hen treatment in HK2 cells.
CONCLUSION: Hen exerts renoprotection effects by regulating AMPK/ULK1-dependent mitophagy, offering a novel therapeutic strategy for the clinical application of Hen.
METHODS: In clinical studies, patients with DKD were treated with Hen and Metformin (MET) for three months to examine their protection against renal injury. In vivo, C57BL/6 mice were subject to streptozotocin and a high-fat diet to induce DKD, followed by Hen (50 mg/kg/d) and MET (200 mg/kg/d) for eight weeks. In vitro, HK2 cells were exposed to high glucose (HG) (30 mM) and Hen (10 μM) for 24h. In rescue experiments, HK2 cells were transfected with sh-AMPK plasmids and subsequently treated with HG and Hen for 24h.
RESULTS: Renal injury and the inhibition of autophagy were both observed in patients with DKD and DKD mice. Consistent with these observations, HG-treated HK2 cells exhibited reduced cell viability and impaired autophagy activity. Hen treatment significantly ameliorated renal injury in DKD mice and enhanced cell viability in HG-treated HK2 cells. Furthermore, Hen exerts its protective effects by activating AMPK/ULK1-mediated mitophagy. Notably, AMPK downregulation effectively inhibited the activation of mitophagy induced by Hen treatment in HK2 cells.
CONCLUSION: Hen exerts renoprotection effects by regulating AMPK/ULK1-dependent mitophagy, offering a novel therapeutic strategy for the clinical application of Hen.