Tang Qiao, Xie Jiatao, Wang Yifei, Dong Chong, Sun Qian
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
The First Clinical College of Wuhan University, Wuhan, China.
Front Immunol. 2025 Feb 5;16:1510500. doi: 10.3389/fimmu.2025.1510500. eCollection 2025.
BACKGROUND: Severe renal ischemia and reperfusion injury (IRI) progresses to renal interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis and macrophage polarization both play important roles in this model, their specific pathogenesis and interactions have not been elucidated. Therefore, we aimed to explore the mechanisms by which ferrotosis occurs in renal tubular epithelial cells (RTECs) and ferroptotic cell-derived exosomes induce macrophage polarization in IRI-related RIF model. METHODS: , C57BL/6J mice were randomly divided into four groups: sham group, ischemia and reperfusion (IR) group, IR + Ferrostatin-1 (Fer-1) group, and IR +ATF3 knockdown (ATF) group. , RTECs were divided into control (CON) group, hypoxia/reoxygenation (HR) group, HR +Fer-1 group, HR + siRNA-ATF3 (siATF3) group. RESULT: Compared with the sham group, the IR group showed more severe kidney injury in HE staining, more collagen fibers in Masson staining, and higher α-SMA expression levels in immunohistochemistry. Total iron and MDA content increased while GSH content decreased. The IR group had more significant mitochondrial damage and higher PTGS2 and TFRC mRNA levels than those in the sham group. Compared with the IR group, the above indexes were all alleviated in the IR+Fer-1 or IR+ATF3 groups. In addition, the protein expressions of ATF3, Nrf2 and HO-1 in the IR group were increased than those in sham group. Compared with the IR group, ATF3 expressions in the IR+Fer-1 or IR+ATF3 groups were decreased, and the protein contents of Nrf2 and HO-1 were further increased. Moreover, there were higher levels of M2 markers (Arg1, TGF-β and IL-10 mRNA) in the IR group than those in the sham group, and lower levels in the IR+Fer-1 group or in the IR+ATF3 group compared with the IR group. The results of experiment are consistent with those of experiment. Mechanistically, the release of exosomes carrying miR-1306-5p by the HR group promoted more M2 macrophage. CONCLUSION: ATF3 might accelerate the ferroptosis by inhibiting Nrf2/ARE pathway, and exosomes from ferroptotic cells reduced the M1/M2 macrophage ratio, promoting fibrosis.
背景：严重的肾缺血再灌注损伤（IRI）会进展为肾间质纤维化（RIF），而治疗策略有限。尽管铁死亡和巨噬细胞极化在该模型中均起重要作用，但其具体发病机制及相互作用尚未阐明。因此，我们旨在探讨肾小管上皮细胞（RTECs）中发生铁死亡的机制以及铁死亡细胞衍生的外泌体在IRI相关RIF模型中诱导巨噬细胞极化的机制。 方法：将C57BL/6J小鼠随机分为四组：假手术组、缺血再灌注（IR）组、IR + 铁死亡抑制剂-1（Fer-1）组和IR + ATF3基因敲低（ATF）组。将RTECs分为对照组（CON）、缺氧/复氧（HR）组、HR + Fer-1组、HR + siRNA-ATF3（siATF3）组。 结果：与假手术组相比，IR组在苏木精-伊红（HE）染色中显示出更严重的肾损伤，在Masson染色中有更多的胶原纤维，免疫组化中α-SMA表达水平更高。总铁和丙二醛（MDA）含量增加，而谷胱甘肽（GSH）含量降低。IR组比假手术组有更明显的线粒体损伤以及更高的前列腺素内过氧化物合酶2（PTGS2）和转铁蛋白受体（TFRC）mRNA水平。与IR组相比，IR+Fer-1或IR+ATF3组的上述指标均得到缓解。此外，IR组中ATF3、核因子E2相关因子2（Nrf2）和血红素加氧酶-1（HO-1）的蛋白表达高于假手术组。与IR组相比，IR+Fer-1或IR+ATF3组中ATF3表达降低，Nrf2和HO-1的蛋白含量进一步增加。此外，IR组中M2标志物（精氨酸酶1（Arg1）、转化生长因子-β（TGF-β）和白细胞介素-10（IL-10）mRNA）水平高于假手术组，与IR组相比，IR+Fer-1组或IR+ATF3组水平较低。实验结果与实验结果一致。机制上，HR组携带miR-1306-5p的外泌体释放促进了更多M2巨噬细胞的产生。 结论：ATF3可能通过抑制Nrf2/ARE途径加速铁死亡，铁死亡细胞来源的外泌体降低了M1/M2巨噬细胞比例，促进纤维化。
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