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Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 μM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg−1·d−1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

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Fig. 1: Effect of Cpd-A1 on erastin-induced ferroptosis and H/R-induced cell injury in mTECs.
Fig. 2: Cpd-A1 suppressed ferroptosis in mTECs with H/R-induced AKI.
Fig. 3: Cpd-A1 attenuated LPS-induced cell damage, inflammatory response and ferroptosis in mTECs.
Fig. 4: Cpd-A1 attenuated I/R-induced AKI, inflammation and ferroptosis in mice.
Fig. 5: Cpd-A1 suppressed kidney injury and ferroptosis in an established AKI mouse model.
Fig. 6: Cpd-A1 attenuated CLP-induced AKI, inflammation and ferroptosis in mice.
Fig. 7: The safety of Cpd-A1 at therapeutic dose.

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Acknowledgements

We acknowledge the Center for Scientific Research of Anhui Medical University and the Inflammation and Immune Mediated Diseases Laboratory of Anhui Province for their valuable help. This work was supported by the National Natural Science Foundation of China (No. 81970584), the promotion plan of basic and clinical cooperative research in Anhui Medical University (No. 2019xkjT014), the Project of Collaborative Innovation for Colleges of Anhui Province (No. GXXT-2021-070), the Major Projects of Science and Technology in Anhui Province (202103a07020013), the Natural Science Foundation of Anhui (2208085QH240), and the Graduate Research and Practice Innovation Project of Anhui Medical University (YJS20230059).

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  1. These authors contributed equally: Ying Chen, Ming-fei Wu, Man-man Xie, Yang Lu.

Authors and Affiliations

  1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, the Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    Ying Chen, Man-man Xie, Chao Li, Shuai-shuai Xie, Wen-xian Ma, Ming-lu Ji, Rui Hou, Ruo-bing He, Meng-meng Zhang, Hao Lu, Jia-gen Wen & Xiao-ming Meng

  2. Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Ming-fei Wu, Yang Lu, Xiao-wu Dong & Jin-xin Che

  3. Department of Pharmacy, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230061, China

    Ze-hui Dong

  4. Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China

    Li Gao

  5. School of Basic Medicine, Anhui Medical University, Hefei, 230032, China

    Juan Jin

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Contributions

YC designed the study, performed the cell experiments, analyzed the data and wrote the manuscript. MFW performed the cell experiments, analyzed the data and wrote the manuscript. MMX and YL. performed the cell experiments analyzed the data. CL, SSX, and WXM performed part of the animal experiments and histological analysis. MLJ, RH, ZHD, RBH, MMZ, HL, and LG performed part of the cellular experiments and histological analysis. JGW, JJ, and XWD provided a series of experimental instructions and help. JXC and XMM provided a series of experimental instructions and wrote the manuscript. All authors have revised and approved the final manuscript.

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Correspondence to Jin-xin Che or Xiao-ming Meng.

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Chen, Y., Wu, Mf., Xie, Mm. et al. Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01277-w

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