Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, China.
Int Immunopharmacol. 2022 Oct;111:109101. doi: 10.1016/j.intimp.2022.109101. Epub 2022 Aug 5.
Cisplatin, as a commonly used anticancer drug, can easily lead to acute kidney injury (AKI), and has received more and more attention in clinical practice. β-hydroxybutyric acid (BHB) is a metabolite in the body and acts as an inhibitor of oxidative stress and NLRP3 inflammasome, reducing inflammatory responses and apoptosis. However, the role of BHB in cisplatin-induced AKI is currently not fully elucidated. In this study, C57BL/6 male mice were randomly divided into normal control group, cisplatin-induced AKI group and AKI with BHB treatment group. Compared to the control, cisplatin-treated mice exhibited high level of serum creatinine, blood urea nitrogen and severe tubular injury, which accompanied with significantly increased expression level of NLRP3, IL-1β, IL-18, BAX, cleaved-caspase 3, as well as aggravated oxidative stress and renal tubular cell apoptosis. However, these changes were significantly improved in that of BHB treatment. In vitro, our study showed that the expression of cleaved-caspase3, IL-1β and IL-18 were significantly increased in human proximal tubular epithelial cell line (HK-2) treated with cisplatin compared with the control group, while decreased in cells treated with BHB. Furthermore, a significantly increased expression of cGAS and STING in HK-2 cells treated with cisplatin were found, whereas notably decreased in cells treated with BHB. This data indicates that BHB protects against cisplatin-induced AKI and renal tubular damage mediated by NLRP3 inflammasome and cGAS-STING pathway.
顺铂作为一种常用的抗癌药物，容易导致急性肾损伤（AKI），在临床实践中越来越受到关注。β-羟丁酸（BHB）是体内的一种代谢物，作为氧化应激和 NLRP3 炎性小体的抑制剂，可减少炎症反应和细胞凋亡。然而，BHB 在顺铂诱导的 AKI 中的作用目前尚未完全阐明。在这项研究中，C57BL/6 雄性小鼠被随机分为正常对照组、顺铂诱导的 AKI 组和 AKI 加 BHB 治疗组。与对照组相比，顺铂处理组的血清肌酐、血尿素氮水平升高，肾小管损伤严重，同时 NLRP3、IL-1β、IL-18、BAX、cleaved-caspase3 的表达水平显著升高，氧化应激和肾小管细胞凋亡加重。然而，BHB 治疗组的这些变化明显改善。体外研究表明，与对照组相比，顺铂处理的人近端肾小管上皮细胞系（HK-2）中 cleaved-caspase3、IL-1β 和 IL-18 的表达明显增加，而 BHB 处理的细胞中表达减少。此外，还发现顺铂处理的 HK-2 细胞中 cGAS 和 STING 的表达显著增加，而 BHB 处理的细胞中表达明显减少。这些数据表明，BHB 可防止顺铂诱导的 AKI 及 NLRP3 炎性小体和 cGAS-STING 通路介导的肾小管损伤。
