Wang Yi-Hui, Chang Dong-Yuan, Zhao Ming-Hui, Chen Min
Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China.
Peking-Tsinghua Center for Life Sciences, Beijing, China.
Antioxid Redox Signal. 2024 Mar;40(7-9):492-509. doi: 10.1089/ars.2022.0169. Epub 2023 Aug 17.
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) showed excellent renoprotective effects; however, the underlying mechanism remains not fully understood. Previous studies have revealed the importance of ferroptosis, which is closely related to oxidative stress, in the progression of DKD. In the current study, we hypothesized that SGLT2i could relieve ferroptosis and thereby alleviate renal injury in DKD due to their antioxidative stress effects. Typical changes of ferroptosis including massive lipid peroxidation, compromised antioxidant capability, and iron overload were found in mice and high glucose/high fat (HG/HF)-treated HK-2 cells. Furthermore, increased expression of hypoxia inducible factor 1α (HIF1α) and heme oxygenase 1 (HO1) was observed in mice and HG/HF-treated HK-2 cells as well. Dapagliflozin treatment significantly ameliorated the ferroptosis-related changes attenuating overactivation of the HIF1α/HO1 axis and . Besides, downregulation of the HIF1α/HO1 axis alleviated ferroptosis, while overexpression of HIF1α and HO1 aggravated ferroptosis induced by HG/HF in HK-2 cells. This study revealed that SGLT2i played a renoprotective role in DKD, at least in part, through alleviating HIF1α/HO1-mediated ferroptosis. 40, 492-509.
糖尿病肾病（DKD）是终末期肾病的主要病因。钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）显示出优异的肾脏保护作用；然而，其潜在机制仍未完全明确。既往研究揭示了铁死亡在DKD进展中的重要性，铁死亡与氧化应激密切相关。在本研究中，我们假设SGLT2i可减轻铁死亡，从而因抗氧化应激作用减轻DKD中的肾损伤。在小鼠和高糖/高脂（HG/HF）处理的HK-2细胞中发现了铁死亡的典型变化，包括大量脂质过氧化、抗氧化能力受损和铁过载。此外，在小鼠和HG/HF处理的HK-2细胞中也观察到缺氧诱导因子1α（HIF1α）和血红素加氧酶1（HO1）的表达增加。达格列净治疗显著改善了与铁死亡相关的变化，减弱了HIF1α/HO1轴的过度激活。此外，HIF1α/HO1轴的下调减轻了铁死亡，而HIF1α和HO1的过表达加重了HG/HF诱导的HK-2细胞铁死亡。本研究表明，SGLT2i在DKD中发挥肾脏保护作用，至少部分是通过减轻HIF1α/HO1介导的铁死亡实现的。40, 492 - 509。
