ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury

Redox Biology

Menghan Zhang¹  Yali Su²  Yanting Lin³  Dayong Zhang³  Qiuhua Cao³  Xinmeng Cui³  Ran Bi³  Chongxiu Yue³  Siliang Liu³  Fei Quan³  Qixiang Zhao³  Yong Yang³  Yue Wang³  Xinghua Gao⁴ 

[1] Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China;Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7568, USA;Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China;School of Sciences, China Pharmaceutical University, Nanjing, 211198, China;

关键词: ACSL4;    Acute kidney injury;    Ferroptosis;    Macrophages;    HIF-1α;   

DOI  :  

来源: DOAJ

【 摘 要 】

The term ferroptosis coined in 2012 causes acute kidney injury (AKI). However, its pathway mechanism in AKI is poorly understood. In this study, we conducted an RNA-sequence analysis of kidneys in AKI and normal mice to explore the pathway mechanism of ferroptosis. Consequently, differentially expressed genes highlighted Acyl-CoA synthetase long-chain family (ACSL4), a known promotor for ferroptosis. Besides, RT-PCR, Western blot, and immunohistochemical analyses confirmed its upregulation. HIF-1α was downregulated in I/R-AKI mice, and in vitro studies confirmed a negative regulation of HIF-1α on ACSL4. To explore the role of ACSL4 in AKI, we constructed ACSL4 knockout in kidney tubules of mice-as Cdh16Cre-ACSL4F/F mice. Results revealed that ACSL4 knockout significantly reduced ferroptosis and inhibited the functional and pathological injury of AKI mice. Meanwhile, the kidneys of Cdh16Cre-ACSL4F/F mice demonstrated a significantly decreased inflammation and macrophage infiltration. Further, additional explorations were explored to decipher a more thorough understanding of ferroptotic immunogenicity. As a result, neutrophils were not directly recruited by ferroptotic cells, but by ferroptotic cell-induced macrophages. Further, ACSL4 inhibitor rosiglitazone significantly inhibited AKI. Collectively, these data provide novel insights into the AKI pathogenesis, and defined ACSL4 as an effective target in AKI.

【 授权许可】

Unknown