Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD  

作　　者：Yunjing Zhang Jicheng Wu Quanlin An Huanhuan Zhu Xinwan Su Ying Wang Xishao Xie Jian Zhang Xi Yao Chunhua Weng Shi Feng Jianhua Mao Xianghui Fu Fei Han Xin Cao Ben Wang Weiqiang Lin 

机构地区：[1]International Institute of Medicine,The Fourth Affiliated Hospital,Zhejiang University School of Medicine,Jinhua 322000,China [2]Institute of Translational Medicine,Zhejiang University,Hangzhou 310029,China [3]Cancer Institute(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education),The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China [4]Zhongshan Hospital Institute of Clinical Science,Fudan University,Shanghai 200032,China [5]Kidney Disease Center,the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003,China [6]Key Laboratory of Kidney Disease Prevention and Control Technology,Zhejiang Province,Hangzhou 310003,China [7]Department of Nephrology,The Children's Hospital,Zhejiang University School of Medicine and National Clinical Research Center for Child Health,Hangzhou 310000,China [8]Division of Endocrinology and Metabolism,National Clinical Research Center for Geriatrics,State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,Chengdu 610041,China

出　　处：《Nano Research》2023年第7期9701-9714,共14页纳米研究（英文版）

基　　金：This work was supported by grants from Zhejiang Provincial Natural Science Foundation of China(No.LZ22H050001);the National Natural Science Foundation of China(Nos.81970573,81670651,81900683,82000637,and 82173662);Zhejiang provincial program for the Cultivation of High-level Innovative Health talents,Natural Science Foundation of Shanghai(No.20ZR1410400);Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(No.2020KY538).

摘　　要：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 AKI in vitro and in vivo via 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 DXZPSA with the enhanced renal distribution.

关 键 词：DEXRAZOXANE dexrazoxane-polysialic acid acute kidney injury ischemia-reperfusion injury ferroptosis α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase(ACMSD) 

分 类 号：R692[医药卫生—泌尿科学]