Journal Article

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis

Ji, Ming-lu, Lu, Hao, Wen, Jia-gen, Chen, Ying, Meng, Xiao-ming, Lu, Yang, Zhang, Meng-meng, Che, Jin-xin, Hou, Rui, Xie, Shuai-shuai, Wu, Ming-fei, Xie, Man-man, Ma, Wen-xian, Dong, Ze-hui, Gao, Li, Jin, Juan, He, Ruo-bing, Li, Chao, Dong, Xiao-wu

2024

Overview

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.

• Publisher: Springer Nature Singapore,Nature Publishing Group
• Subject: Acute Kidney Injury - drug therapy / Acute Kidney Injury - metabolism / Animal models / Animals / Biomedical and Life Sciences / Biomedicine / Cecum / Cell death / Creatinine / Cyclohexylamines - pharmacology / Cyclohexylamines - therapeutic use / Epithelial cells / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Ferroptosis / Ferroptosis - drug effects / Hypoxia / Immunology / Internal Medicine / Ischemia / Kidneys / Male / Medical Microbiology / Mice / Mice, Inbred C57BL / Oxidative stress / Pharmacokinetics / Pharmacology/Toxicology / Phenylenediamines - pharmacology / Phenylenediamines - therapeutic use / Renal function / Reperfusion / Reperfusion Injury - drug therapy / Reperfusion Injury - metabolism / Vaccine