ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury

  • Redox Biol. 2022 May;51:102262. doi: 10.1016/j.redox.2022.102262.
Yue Wang  1 ,  Menghan Zhang  2 ,  Ran Bi  3 ,  Yali Su  3 ,  Fei Quan  3 ,  Yanting Lin  3 ,  Chongxiu Yue  3 ,  Xinmeng Cui  3 ,  Qixiang Zhao  3 ,  Siliang Liu  3 ,  Yong Yang  3 ,  Dayong Zhang  4 ,  Qiuhua Cao  5 ,  Xinghua Gao  6
Affiliations
  • 1. Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China; Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
  • 2. Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China; Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7568, USA.
  • 3. Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China.
  • 4. School of Sciences, China Pharmaceutical University, Nanjing, 211198, China.
  • 5. Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China. Electronic address: [email protected].
  • 6. Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, 211198, PR China. Electronic address: [email protected].
PMID: 35180475 DOI: 10.1016/j.redox.2022.102262
Abstract

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.

Keywords
ACSL4; Acute kidney injury; Ferroptosis; HIF-1α; Macrophages.
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