Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South Korea.
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, South Korea.
Redox Biol. 2022 Aug;54:102382. doi: 10.1016/j.redox.2022.102382. Epub 2022 Jun 23.
The side effects of cisplatin, a widely used chemotherapeutic agent, include nephrotoxicity. Previous studies have reported that cisplatin induces ferroptosis and lipid peroxide accumulation. Ferroptosis, a type of regulated cell death, is characterized by iron-dependent lipid peroxidation. Although previous studies have examined the regulation of ferroptosis in acute kidney injury (AKI), the regulatory mechanism of ferroptosis has not been elucidated. Here, the ability of activated farnesoid X receptor (FXR) to attenuate cisplatin-induced AKI through the regulation of ferroptosis was examined. FXR deficiency exhibited more ferroptosis responses, such as increase in lipid peroxidation, iron content and heme oxygenase 1 protein, and a decrease in glutathione/glutathione disulfide ratio and glutathione peroxidase 4 levels in HK2 cells and mice. Increased blood urea nitrogen, serum creatinine, and ferroptotic responses in the cisplatin-induced AKI mouse model were mitigated upon treatment with the FXR agonist GW4064 but were exacerbated in FXR knockout mice. RNA sequencing analysis revealed that ferroptosis-associated genes were novel targets of FXR. FXR agonist upregulated the expression of lipid and glutathione metabolism-related genes and downregulated cell death-related genes. Additionally, chromatin immunoprecipitation assays, using mice renal tissues, revealed that agonist-activated FXR could bind to its known target genes (Slc51a, Slc51b, Osgin1, and Mafg) and ferroptosis-related genes (Aifm2, Ggt6, and Gsta4). Furthermore, activated FXR-dependent MAFG, a transcriptional repressor, could bind to Hmox1, Nqo1, and Tf in the renal tissues of FXR agonist-treated mice. These findings indicate that activated FXR regulates the transcription of ferroptosis-related genes and protects against cisplatin-induced AKI.
顺铂是一种广泛应用的化疗药物，其副作用包括肾毒性。先前的研究报告称，顺铂诱导铁死亡和脂质过氧化物积累。铁死亡是一种受调控的细胞死亡方式，其特征是铁依赖性脂质过氧化。虽然先前的研究已经检查了急性肾损伤（AKI）中铁死亡的调节，但铁死亡的调节机制尚未阐明。在这里，研究了激活的法尼醇 X 受体（FXR）通过调节铁死亡来减轻顺铂诱导的 AKI 的能力。FXR 缺乏表现出更多的铁死亡反应，例如脂质过氧化、铁含量和血红素加氧酶 1 蛋白增加，谷胱甘肽/谷胱甘肽二硫化物比和谷胱甘肽过氧化物酶 4 水平降低在 HK2 细胞和小鼠中。用 FXR 激动剂 GW4064 治疗可减轻顺铂诱导的 AKI 小鼠模型中的血尿素氮、血清肌酐和铁死亡反应，但在 FXR 敲除小鼠中则加剧。RNA 测序分析表明，铁死亡相关基因是 FXR 的新靶标。FXR 激动剂上调脂质和谷胱甘肽代谢相关基因的表达，下调细胞死亡相关基因的表达。此外，使用小鼠肾组织的染色质免疫沉淀测定表明，激动剂激活的 FXR 可以与已知的靶基因（Slc51a、Slc51b、Osgin1 和 Mafg）和铁死亡相关基因（Aifm2、Ggt6 和 Gsta4）结合。此外，激活的 FXR 依赖性 MAFG，一种转录抑制因子，可以与顺铂激动剂治疗小鼠肾组织中的 Hmox1、Nqo1 和 Tf 结合。这些发现表明，激活的 FXR 调节铁死亡相关基因的转录，并防止顺铂诱导的 AKI。
