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

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Abstract

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 suppressing α-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.

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Acknowledgments

This study was supported by the Core Facility, Zhejiang University School of Medicine. 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) and Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (No. 2020KY538).

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Author notes

  1. Yunjing Zhang and Jicheng Wu contributed equally to this work.

Authors and Affiliations

  1. International Institute of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Jinhua, 322000, China

    Yunjing Zhang, Xinwan Su, Ying Wang & Weiqiang Lin

  2. Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China

    Yunjing Zhang, Jicheng Wu & Ben Wang

  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

    Jicheng Wu & Ben Wang

  4. Zhongshan Hospital Institute of Clinical Science, Fudan University, Shanghai, 200032, China

    Quanlin An & Xin Cao

  5. Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

    Huanhuan Zhu, Xishao Xie, Jian Zhang, Xi Yao, Chunhua Weng, Shi Feng & Fei Han

  6. Key Laboratory of Kidney Disease Prevention and Control Technology, Zhejiang Province, Hangzhou, 310003, China

    Huanhuan Zhu, Xishao Xie, Jian Zhang & Xi Yao

  7. Department of Nephrology, The Children’s Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, 310000, China

    Jianhua Mao

  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

    Xianghui Fu

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  1. Yunjing Zhang
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Correspondence to Fei Han, Xin Cao, Ben Wang or Weiqiang Lin.

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Zhang, Y., Wu, J., An, Q. et al. Renal tubule-targeted dexrazoxane suppresses ferroptosis in acute kidney injury by inhibiting ACMSD. Nano Res. 16, 9701–9714 (2023). https://doi.org/10.1007/s12274-023-5547-8

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  • DOI: https://doi.org/10.1007/s12274-023-5547-8

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