Li Xialin, Hu Yan, Li Jinqing, Shi Yingfeng, Zhong Qin, Ma Xiaoyan, Jiang Daofang, Zhang Shasha, Zhuang Shougang, Liu Na
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, RI, USA.
Ren Fail. 2025 Dec;47(1):2561218. doi: 10.1080/0886022X.2025.2561218. Epub 2025 Sep 18.
This study aimed to elucidate the role and function of roxadustat, a small molecule hypoxia-inducible factor (HIF) stabilizer, on cisplatin-induced acute kidney injury (AKI) and .
We investigated the effects of roxadustat (10 mg/kg) in a cisplatin-induced AKI model in mice. After a 48-hour pretreatment with the intraperitoneal injection of roxadustat, cisplatin was administered at a dose of 20 mg/kg by intraperitoneal injection. We also examined the role of roxadustat (10 μM) on HK-2 cells stimulated by cisplatin (20 μg/mL).
Pretreatment with roxadustat significantly improved kidney function in the AKI model, as evidenced by reductions of Scr and BUN, and alleviated cisplatin-induced kidney morphology lesions. Roxadustat also remarkably decreased the expression of KIM-1 and NGAL. Furthermore, roxadustat significantly abolished the expression of Bax and cleaved caspase 3, two apoptosis marker proteins. Mechanistically, our study demonstrated that roxadustat could alleviate the deficiency of fatty acid oxidation (FAO) induced by cisplatin, as evidenced by the improvement of lipid accumulation and metabolic disorders in the roxadustat-treated group. Moreover, roxadustat effectively blocked mitochondrial damage, as evidenced by reduced mitochondrial swelling and fragmentation in the roxadustat-treated group. Simultaneously, roxadustat also partially rescued the expression of mitochondrial fusion proteins, including OPA1, MFN1, and MFN2. , roxadustat also effectively alleviate injury, apoptotic responses, FAO disorders, mitochondrial damage caused by cisplatin.
We demonstrated that roxadustat exerts a protective role in cisplatin-treated mice and HK-2 cells, which might be due to amelioration of FAO deficiency and suppression of mitochondrial damage.
本研究旨在阐明小分子缺氧诱导因子（HIF）稳定剂罗沙司他对顺铂诱导的急性肾损伤（AKI）的作用和功能。
我们在顺铂诱导的小鼠急性肾损伤模型中研究了罗沙司他（10mg/kg）的作用。在腹腔注射罗沙司他进行48小时预处理后，腹腔注射20mg/kg剂量的顺铂。我们还研究了罗沙司他（10μM）对顺铂（20μg/mL）刺激的HK-2细胞的作用。
罗沙司他预处理显著改善了急性肾损伤模型中的肾功能，表现为血清肌酐（Scr）和尿素氮（BUN）降低，并减轻了顺铂诱导的肾脏形态学损伤。罗沙司他还显著降低了肾损伤分子-1（KIM-1）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的表达。此外，罗沙司他显著消除了凋亡标记蛋白Bax和裂解的半胱天冬酶-3的表达。从机制上讲，我们的研究表明，罗沙司他可以减轻顺铂诱导的脂肪酸氧化（FAO）缺陷，罗沙司他治疗组脂质积累和代谢紊乱的改善证明了这一点。此外，罗沙司他有效阻断了线粒体损伤，罗沙司他治疗组线粒体肿胀和碎片化减少证明了这一点。同时，罗沙司他还部分挽救了线粒体融合蛋白的表达，包括视神经萎缩蛋白1（OPA1）、线粒体融合蛋白1（MFN1）和线粒体融合蛋白2（MFN2）。此外，罗沙司他还有效减轻了顺铂引起的损伤、凋亡反应、FAO紊乱和线粒体损伤。
我们证明罗沙司他在顺铂处理的小鼠和HK-2细胞中发挥保护作用，这可能是由于改善了FAO缺陷和抑制了线粒体损伤。
