Journal Article

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

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

2023

Overview

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.

• Publisher: Tsinghua University Press
• Subject: 4-Hydroxynonenal / Atomic/Molecular Structure and Spectra / Biomarkers / Biomedicine / Biotechnology / Chemistry and Materials Science / Cisplatin / Condensed Matter Physics / Conjugation / Ferritin / Ferroptosis / Glutathione / Glutathione peroxidase / Injuries / Ischemia / Kidneys / Lipid peroxidation / Lipids / Materials Science / Molecular modelling / Nanotechnology / Oxidative stress / Peroxidase / Peroxidation / Polysialic acid / Razoxane / Renal tubules / Reperfusion / Research Article