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Research Article

Targeting iron metabolism using gallium nanoparticles to suppress ferroptosis and effectively mitigate acute kidney injury

Xishao Xie1,§, Yunjing Zhang2,3,§, Xinwan Su2, Junni Wang1, Xi Yao1, Dou Lv4, Qin Zhou1, Jianhua Mao5, Jianghua Chen1, Fei Han1( ), Yangyang Li6,7( ), Weiqiang Lin2( )
Kidney Disease Center, the First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou 310003, China
International Institutes of Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Jinhua 322000, China
Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China
Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University College of Medicine; Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Hangzhou 310003, China
Department of Nephrology, National Clinical Research Center For Child Health, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
Key Laboratory of Women’s Reproductive Health Research of Zhejiang Province, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
Cancer Center, Zhejiang University, Hangzhou 310058, China

§ Xishao Xie and Yunjing Zhang contributed equally to this work.

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Graphical Abstract

Here, novel gallic acid-gallium polyvinyl pyrrolidone nanoparticles (GGP NPs) are developed as a potential iron-scavenging agent, which can reduce intracellular free iron and inhibit ferroptosis, showing notable renoprotective effects against cisplatin-induced or ischemic acute kidney injury (AKI).

Abstract

Ferroptosis plays a critical pathophysiological role in several types of acute kidney injury (AKI). The development of nanomaterials targeting iron metabolism and ferroptosis is a promising approach for AKI treatment. Herein, we synthesized gallic acid-gallium polyvinyl pyrrolidone nanoparticles (GGP NPs) as a potential iron-scavenging agent because of their nearly ionic radius and chemical similarity with iron. The results indicated that GGP NPs accumulated in tubular epithelial cells and showed good biocompatibility. GGP NPs significantly inhibited cisplatin (CP)-induced ferroptosis in HK-2 cells by reducing the accumulation of intracellular free iron and mitochondrial dysfunction, and suppressing the perturbations of ferroptosis processes, including lipid peroxidation, nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) levels, glutathione peroxidase 4 (GPX4) activity, and ferritinophagy. An in vivo study demonstrated that treatment with GGP NPs significantly ameliorated the renal tubular injury and mitochondrial damage induced by CP treatment or ischemia-reperfusion injury. Our study suggests that GGP NPs may be an effective and promising candidate for AKI treatment and enable potential clinical translation.

Keywords

gallium nanoparticlesacute kidney injuryischemia-reperfusion injuryiron metabolismferroptosis

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Nano Research
Volume 15 Issue 7,
July 2022
Pages 6315-6327
DOI: 10.1007/s12274-022-4257-y
Cite this article:
Xie X, Zhang Y, Su X, et al. Targeting iron metabolism using gallium nanoparticles to suppress ferroptosis and effectively mitigate acute kidney injury. Nano Research, 2022, 15(7): 6315-6327. https://doi.org/10.1007/s12274-022-4257-y
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Received: 21 December 2021
Revised: 17 February 2022
Accepted: 20 February 2022
Published: 04 May 2022
© Tsinghua University Press 2022
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