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Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis

   
@article{APS11072,
	author = {Ying Chen and Ming-fei Wu and Man-man Xie and Yang Lu and Chao Li and Shuai-shuai Xie and Wen-xian Ma and Ming-lu Ji and Rui Hou and Ze-hui Dong and Ruo-bing He and Meng-meng Zhang and Hao Lu and Li Gao and Jia-gen Wen and Juan Jin and Xiao-wu Dong and Jin-xin Che and Xiao-ming Meng},
	title = {Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis},
	journal = {Acta Pharmacologica Sinica},
	volume = {45},
	number = {8},
	year = {2024},
	keywords = {},
	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.},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/11072}
}