Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD
Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD
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DOI：
10.1007/s12274-023-5547-8
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发表时间：
2023-04
期刊：
影响因子：
9.9
通讯作者：
Yunjing Zhang;Jicheng Wu;Quanlin An;Huanhuan Zhu;Xinwan Su;Ying Wang;Xi-shao Xie;Jian Zhang;Xiaoli Yao;Chunhua Weng;S. Feng;Jianhua Mao;Xianghui Fu;Fei Han;Xin Cao;Ben Wang;Weiqiang Lin
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作者：
Yunjing Zhang;Jicheng Wu;Quanlin An;Huanhuan Zhu;Xinwan Su;Ying Wang;Xi-shao Xie;Jian Zhang;Xiaoli Yao;Chunhua Weng;S. Feng;Jianhua Mao;Xianghui Fu;Fei Han;Xin Cao;Ben Wang;Weiqiang Lin
急性肾损伤（AKI）是一种异质性临床并发症，目前尚无明确或特定的治疗方法。因此，迫切需要治疗急性肾损伤的分子机制和方法。在此，我们证明了右雷佐生 (DXZ) 是一种美国食品和药物管理局 (FDA) 批准的心脏保护药物，可以通过特异性抑制铁死亡，在体外和体内在功能和组织学上减弱顺铂或缺血再灌注损伤诱导的 AKI。这种作用的特点是减少脂质过氧化，由氧化应激生物标志物 4-羟基壬烯醛 (HNE) 和前列腺素内过氧化物合酶 2 (Ptgs2) 显示，同时逆转谷胱甘肽过氧化物酶 4 (GPX4) 和铁蛋白 1 (FTH-1) 的下调。从机制上讲，结果表明，靶向肾小管的 DXZ 通过抑制 α-氨基-β-羧基粘康酸-ε-半醛脱羧酶 (ACMSD) 显着抑制铁死亡。此外，右雷佐生和聚唾液酸（DXZ-PSA）的结合物经过专门设计和利用，通过在肾脏中的长期作用，特别是在肾小管中的保留和靶向来增强DXZ的治疗效果。这项研究通过增强肾脏分布的新型药物 DXZ-PSA 来抑制铁死亡，为 AKI 提供了一种新的治疗方法和机制见解。
Acute kidney injury (AKI) is a heterogeneous clinical complication with no existing definite or particular therapies. Therefore, molecular mechanisms and approaches for treating acute kidney injury are in urgent need. Herein, we demonstrated that dexrazoxane (DXZ), a U.S. Food and Drug Administration (FDA)-approved cardioprotective drug, can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKIin vitroandin vivovia inhibiting ferroptosis specifically. This effect is characterized by decreasing lipid peroxidation, shown by the biomarker of oxidative stress 4-hydroxynonenal (HNE) and prostaglandinendoperoxide synthase 2 (Ptgs2), while reversing the downregulation of glutathione peroxidase 4 (GPX4) and ferritin 1 (FTH-1). Mechanistically, the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressingα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD). Furthermore, the conjugation of dexrazoxane and polysialic acid (DXZ-PSA) is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney, especially retention and targeting in the renal tubules. This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZ-PSA with the enhanced renal distribution.