FBXW7-Mediated Downregulation of GPX4 Aggravates Acute Kidney Injury Following Ischemia‒Reperfusion.

Autor: Zhang LM; Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050100, Hebei, China.; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China.; Institute of Microcirculation, Hebei North University, Zhangjiakou, China., Liu XM; Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050100, Hebei, China.; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China., Guo DW; Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050100, Hebei, China.; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China., Li F; Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050100, Hebei, China.; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China., Hao J; Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050100, Hebei, China.; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China.; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China., Zhao S; Department of Pathology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050100, Hebei, China. 17200558@hebmu.edu.cn.; Hebei Key Laboratory of Kidney Diseases, Shijiazhuang, China. 17200558@hebmu.edu.cn.; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science of Hebei Medical University, Shijiazhuang, China. 17200558@hebmu.edu.cn.
Jazyk: angličtina
Zdroj: Inflammation [Inflammation] 2024 Aug 29. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1007/s10753-024-02137-9
Abstrakt: Acute kidney injury (AKI) is a prevalent and potentially life-threatening complication characterized by a high incidence and mortality. A large number of studies have emphasized the role of ferroptosis in AKI. Moreover, FBXW7, a ubiquitin ligase, has been implicated in acute organ injury. Analysis of the GEO database (GSE98622) revealed increased FBXW7 mRNA levels in the kidney following ischemia‒reperfusion (IR). However, the role of FBXW7 in AKI has not been elucidated. Therefore, this study aimed to investigate the role of FBXW7 in IR-AKI and its underlying mechanisms. Here, we found that IR could induce AKI and increase FBXW7 expression, while the ferroptosis inhibitor Fer-1 alleviated AKI and decreased FBXW7 expression. Furthermore, we treated HK-2 cells with hypoxia for 12 h and reoxygenation for 4 h (H12R4) to simulate IR-AKI and investigated the impact of modulating FBXW7 expression on ferroptosis by employing ferroptosis-related agonists or inhibitors. Our findings revealed that H12R4 induced HK2 ferroptosis and increased the expression of FBXW7. FBXW7 overexpression in control cells exacerbated erastin-induced ferroptosis, and FBXW7 knockdown inhibited ferroptosis in H12R4-treated cells. Mechanistically, we confirmed that FBXW7 can bind to GPX4, a key molecule that inhibits ferroptosis. The half-life of the GPX4 protein decreased after FBXW7 overexpression, GPX4 ubiquitination increased after H12R4, and GPX4 degradation decreased after FBXW7 knockdown. In conclusion, our results indicated that FBXW7 plays an important role in the development of IR-AKI by promoting ferroptosis through the downregulation of GPX4 expression. This study provides new insight into FBXW7 as a potential target for treating AKI.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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