2. Academic Validation
  3. Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis

  • Acta Pharmacol Sin. 2024 Apr 19. doi: 10.1038/s41401-024-01277-w.
Ying Chen # 1,  Ming-Fei Wu # 2,  Man-Man Xie # 1,  Yang Lu # 2,  Chao Li 1,  Shuai-Shuai Xie 1,  Wen-Xian Ma 1,  Ming-Lu Ji 1,  Rui Hou 1,  Ze-Hui Dong 3,  Ruo-Bing He 1,  Meng-Meng Zhang 1,  Hao Lu 1,  Li Gao 4,  Jia-Gen Wen 1,  Juan Jin 5,  Xiao-Wu Dong 2,  Jin-Xin Che 6,  Xiao-Ming Meng 7
Affiliations

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.
  • 2 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 3 Department of Pharmacy, The Second Affiliated Hospital of Anhui University of Traditional Chinese Medicine, Hefei, 230061, China.
  • 4 Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
  • 5 School of Basic Medicine, Anhui Medical University, Hefei, 230032, China.
  • 6 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. chejx@zju.edu.cn.
  • 7 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. mengxiaoming@ahmu.edu.cn.
  • # Contributed equally.
PMID: 38641746 DOI: 10.1038/s41401-024-01277-w
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.

Keywords

AKI; Cpd-A1; ferroptosis; ferrostatin-1; lipid peroxidation; tissue distribution.

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