急性肾损伤(AKI)是一种常见且潜在危及生命的并发症,其特征是发病率和死亡率高。大量研究强调了铁凋亡在AKI中的作用。此外,FBXW7,一种泛素连接酶,与急性器官损伤有关.对GEO数据库(GSE98622)的分析显示,缺血再灌注(IR)后肾脏中FBXW7mRNA水平升高。然而,FBXW7在AKI中的作用尚未阐明.因此,本研究旨在探讨FBXW7在IR-AKI中的作用及其机制。这里,我们发现IR可以诱导AKI并增加FBXW7的表达,而铁凋亡抑制剂Fer-1减轻了AKI并降低了FBXW7的表达。此外,我们用缺氧12小时和复氧4小时(H12R4)处理HK-2细胞以模拟IR-AKI,并研究了通过使用与铁凋亡相关的激动剂或抑制剂调节FBXW7表达对铁凋亡的影响.我们的发现表明H12R4诱导HK2铁凋亡并增加FBXW7的表达。FBXW7在对照细胞中的过表达加剧了擦除素诱导的铁细胞凋亡,和FBXW7敲低抑制H12R4处理的细胞中的铁凋亡。机械上,我们证实FBXW7可以与GPX4结合,GPX4是抑制铁细胞凋亡的关键分子。FBXW7过表达后,GPX4蛋白的半衰期降低,H12R4后GPX4泛素化增加,FBXW7敲低后GPX4降解减少。总之,我们的结果表明,FBXW7通过下调GPX4的表达促进铁凋亡,在IR-AKI的发展中起重要作用。这项研究为FBXW7作为治疗AKI的潜在靶标提供了新的见解。
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.