Li Xinyuan, Chen Guo, Zhou Xiang, Peng Xiang, Li Mao, Chen Daihui, Yu Haitao, Shi Wei, Zhang Chunlin, Li Yang, Feng Zhenwei, Mei Yuhua, Li Li, Liang Simin, He Weiyang, Gou Xin, Li Jie
Department of Urology The First Affiliated Hospital of Chongqing Medical University Chongqing China.
CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences Shanghai China.
Smart Med. 2024 Apr 2;3(2):e20230043. doi: 10.1002/SMMD.20230043. eCollection 2024 Jun.
Ferroptosis is a predominant contributor to graft kidney ischemia‒reperfusion injury (IRI), resulting in delayed graft function (DGF). However, much less is known about the early predicting biomarkers and therapeutic targets of DGF, especially aiming at ferroptosis. Here, we propose a precise predicting model for DGF, relying on the Akirin1 level in extracellular vesicles (EVs) derived from recipient urine 48 h after kidney transplant. In addition, we decipher a new molecular mechanism whereby Akirin1 induces ferroptosis by strengthening TP53-mediated suppression of SLC7A11 during the graft kidney IRI process, that is, Akirin1 activates the EGR1/TP53 axis and inhibits MDM2-mediated TP53 ubiquitination, accordingly upregulating TP53 in two ways. Meanwhile, we present the first evidence that miR-136-5p enriched in EVs secreted by human umbilical cord mesenchymal stem cells (UM-EVs) confers robust protection against ferroptosis and graft kidney IRI by targeted inhibition of Akirin1 but knockout of miR-136-5p in UM sharply mitigates the protection of UM-EVs. The functional and mechanistic regulation of Akirin1 is further corroborated in an allograft kidney transplant model in wild-type and Akirin1-knockout mice. In summary, these findings suggest that Akirin1, which prominently induces ferroptosis, is a pivotal biomarker and target for early diagnosis and treatment of graft kidney IRI and DGF after kidney transplant.
铁死亡是移植肾缺血再灌注损伤（IRI）的主要促成因素，可导致移植肾功能延迟恢复（DGF）。然而，对于DGF的早期预测生物标志物和治疗靶点，尤其是针对铁死亡的相关研究却知之甚少。在此，我们提出了一种针对DGF的精准预测模型，该模型依赖于肾移植术后48小时受者尿液来源的细胞外囊泡（EVs）中的Akirin1水平。此外，我们还解析了一种新的分子机制，即Akirin1在移植肾IRI过程中通过增强TP53介导的对SLC7A11的抑制作用来诱导铁死亡，也就是说，Akirin1激活EGR1/TP53轴并抑制MDM2介导的TP53泛素化，从而以两种方式上调TP53。同时，我们首次证明，富集于人脐带间充质干细胞分泌的EVs（UM-EVs）中的miR-136-5p通过靶向抑制Akirin1赋予对铁死亡和移植肾IRI的强大保护作用，但敲除UM中的miR-136-5p会显著减轻UM-EVs的保护作用。在野生型和Akirin1基因敲除小鼠的同种异体肾移植模型中，进一步证实了Akirin1的功能和机制调控。总之，这些发现表明，显著诱导铁死亡的Akirin1是肾移植后移植肾IRI和DGF早期诊断和治疗的关键生物标志物和靶点。
