Du Yiwei, Feng Chunni, Zhou Lu, Wang Tingting, Ma Heng, Liu Hongbao
Department of Nephrology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, 710038, China.
Renal Division, Peking University Institute of Nephrology, Key Laboratory of Renal Disease-Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment (Peking University)-Ministry of Education of China, Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases-Chinese Academy of Medical Sciences, Peking University First Hospital, Xishiku Street #8, Beijing, 100034, China.
Commun Biol. 2025 Jul 28;8(1):1112. doi: 10.1038/s42003-025-08455-4.
Ferroptosis is involved in the occurrence and progression of renal ischemia/reperfusion (I/R) injury. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that is closely associated with kidney diseases. However, the underlying mechanisms between MIF and ferroptosis in acute kidney injury (AKI) still remain unclear. In contrast to conventional strategies, we further investigate the dynamic expression and role of MIF in both ischemic and reperfusion phases. In the present study, we establish hypoxia/reoxygenation (H/R) and I/R induced AKI models, verify ferroptosis by detecting pro-ferroptotic changes and associated indicators, and use si-RNA or Adeno-Associated virus (AAV) to knock down the expression of MIF, observing subsequent changes of ferroptosis. The results show that treatment with recombinant MIF reduces lipid ROS generation and MDA levels, upregulating glutathione (GSH) levels, with increasing AMP-activated protein kinase (AMPK) phosphorylation. While the deficiency of MIF blunted its protective effect on renal tubular epithelial cells, which demonstrates that MIF ameliorates ferroptosis injury via activating the AMPK pathway in the ischemia stage and increasing GSH content in the reperfusion stage. In conclusion, our results suggest the nephroprotective role of MIF in inhibiting ferroptosis and provide insight into the prevention and treatment of AKI.
铁死亡参与肾缺血/再灌注（I/R）损伤的发生和发展。巨噬细胞移动抑制因子（MIF）是一种多效性细胞因子，与肾脏疾病密切相关。然而，急性肾损伤（AKI）中MIF与铁死亡之间的潜在机制仍不清楚。与传统策略不同，我们进一步研究了MIF在缺血和再灌注阶段的动态表达及作用。在本研究中，我们建立了缺氧/复氧（H/R）和I/R诱导的AKI模型，通过检测促铁死亡变化及相关指标来验证铁死亡，并使用小干扰RNA（si-RNA）或腺相关病毒（AAV）敲低MIF的表达，观察随后铁死亡的变化。结果显示，重组MIF处理可减少脂质活性氧生成和丙二醛水平，上调谷胱甘肽（GSH）水平，并增加AMP激活的蛋白激酶（AMPK）磷酸化。而MIF缺乏则减弱了其对肾小管上皮细胞的保护作用，这表明MIF在缺血阶段通过激活AMPK途径、在再灌注阶段通过增加GSH含量来减轻铁死亡损伤。总之，我们的结果表明MIF在抑制铁死亡方面具有肾保护作用，并为AKI的防治提供了思路。
