Cobaltosic oxide-polyethylene glycol-triphenylphosphine nanoparticles ameliorate the acute-to-chronic kidney disease transition by inducing BNIP3-mediated mitophagy.

Shaozong Qin, Chi Liu, Yin Chen, Mengying Yao, Shuyi Liao, Wang Xin, Shuiqin Gong, Xu Guan, Yan Li, Jiachuan Xiong, Jing Chen, Yunzhu Shen, Yong Liu, Jinghong Zhao, Yinghui Huang

Kidney international 2023 May

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Accumulating evidence highlights mitochondrial dysfunction as a crucial factor in the pathogenesis of acute kidney injury (AKI); thus, novel therapeutic strategies maintaining mitochondrial homeostasis are highly anticipated. Recent studies have shown that cobaltosic oxide has peroxidase-like catalytic activities, although its role and mechanism remain elusive in AKI. In the present study, we synthesized and identified cobaltosic oxide-polyethylene glycol-triphenylphosphine (COPT) nanoparticles by conjugating cobaltosic oxide with polyethylene glycol and triphenylphosphine, to improve its biocompatibility and mitochondria-targeting property. We found that COPT preferentially accumulated in the kidney proximal tubule cells, and significantly alleviated ischemic AKI in mouse models and gentamicin induced-AKI in the zebrafish model. COPT also inhibited the transition from AKI to chronic kidney disease (CKD), with few side effects. Further studies demonstrated that COPT localized in the mitochondria, and ameliorated hypoxia-reoxygenation-mediated mitochondrial damage through enhancing mitophagy in vitro and in vivo. Mechanistically, COPT dose-dependently induced the expression of Bcl-2/adenovirus E1B 19-kDa interacting protein (BNIP3), while knockdown of BNIP3 attenuated COPT-induced mitophagic flux and mitochondrial protection. Thus, our findings suggest that COPT nanoparticles ameliorate AKI and its progression to CKD through inducing BNIP3-mediated mitophagy, indicating that COPT may serve as a promising mitochondria-targeting therapeutic agent against AKI. Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Citation

Shaozong Qin, Chi Liu, Yin Chen, Mengying Yao, Shuyi Liao, Wang Xin, Shuiqin Gong, Xu Guan, Yan Li, Jiachuan Xiong, Jing Chen, Yunzhu Shen, Yong Liu, Jinghong Zhao, Yinghui Huang. Cobaltosic oxide-polyethylene glycol-triphenylphosphine nanoparticles ameliorate the acute-to-chronic kidney disease transition by inducing BNIP3-mediated mitophagy. Kidney international. 2023 May;103(5):903-916