Carnosol alleviates cisplatin–induced acute kidney injury by regulating apoptosis and pyroptosis

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Chunjie Li, Hongyan Yang, Yuan Wu, Mingke Zhou, Hengbiao Luo, Peng Yuan, Fengge Shen
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引用次数: 0

Abstract

The use of the common anticancer drug cisplatin (CP) in clinical practice often leads to acute kidney injury (AKI); however, no protective therapy is available. Therefore, new drugs that reduce the nephrotoxicity induced by CP are urgently needed. Carnosol (CA) is an antioxidant found. We investigated the renoprotective effects of CA on CP-induced AKI in male C57BL/6 mice and HK2 cells. CA mitigated renal dysfunction, histopathological changes and tubular injury in vivo, as indicated by the expression of NGAL, KIM1 and HMGB1. Moreover, the numbers of apoptotic cells and the expression of apoptotic proteins were dramatically reduced after CA treatment in mouse kidneys and HK2 cells. CA significantly ameliorated CP-induced inflammation and decreased TNF-α and IL-1β levels in vivo and in vitro and macrophage infiltration in the mouse kidney. CA decreased the expression levels of p-p65/p65, NLRP3 and ASC, which indicates that CA suppressed the activation of the NF-κB/NLRP3 signaling axis induced by CP in vivo and in vitro. In addition, CA decreased the levels of certain protein in pyroptotic cells, as indicated by the expression of cleaved caspase-1, GSDMD, and mature IL-1β and IL-18 in vivo and in vitro. Finally, CA reduced the level of cleaved caspase-1, but those of GSDMD and NLRP3 protein were not significantly different after treatment with the NLRP3 inhibitor MCC950 and were elevated by the NLRP3 activator nigericin. In conclusion, this study revealed that CA protects against CP-induced AKI by decreasing apoptosis and NF-κB/NLRP3/GSDMD-mediated pyroptosis, which provides new insight into the prevention of AKI.

卡诺索尔通过调节细胞凋亡和热解减轻顺铂诱导的急性肾损伤
在临床实践中,使用常见的抗癌药物顺铂(CP)常常会导致急性肾损伤(AKI);然而,目前还没有保护性疗法。因此,迫切需要能降低顺铂引起的肾毒性的新药。卡诺索尔(Carnosol,CA)是一种抗氧化剂。我们在雄性 C57BL/6 小鼠和 HK2 细胞中研究了 CA 对氯化石蜡诱导的 AKI 的肾保护作用。从 NGAL、KIM1 和 HMGB1 的表达来看,CA 可减轻体内肾功能障碍、组织病理变化和肾小管损伤。此外,小鼠肾脏和 HK2 细胞经 CA 处理后,凋亡细胞的数量和凋亡蛋白的表达均显著减少。CA能明显改善CP诱导的炎症反应,降低体内和体外TNF-α和IL-1β的水平以及小鼠肾脏中巨噬细胞的浸润。CA降低了p-p65/p65、NLRP3和ASC的表达水平,这表明CA抑制了体内和体外CP诱导的NF-κB/NLRP3信号轴的激活。此外,CA 还降低了脓细胞中某些蛋白质的水平,体内和体外的裂解 Caspase-1、GSDMD 以及成熟 IL-1β 和 IL-18 的表达均表明了这一点。最后,CA降低了裂解的caspase-1的水平,但GSDMD和NLRP3蛋白的水平在NLRP3抑制剂MCC950处理后无明显差异,而在NLRP3激活剂尼格列汀处理后则升高。总之,本研究揭示了CA通过减少细胞凋亡和NF-κB/NLRP3/GSDMD介导的热蛋白沉积对CP诱导的AKI具有保护作用,这为预防AKI提供了新的思路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Biology International
Cell Biology International 生物-细胞生物学
CiteScore
7.60
自引率
0.00%
发文量
208
审稿时长
1 months
期刊介绍: Each month, the journal publishes easy-to-assimilate, up-to-the minute reports of experimental findings by researchers using a wide range of the latest techniques. Promoting the aims of cell biologists worldwide, papers reporting on structure and function - especially where they relate to the physiology of the whole cell - are strongly encouraged. Molecular biology is welcome, as long as articles report findings that are seen in the wider context of cell biology. In covering all areas of the cell, the journal is both appealing and accessible to a broad audience. Authors whose papers do not appeal to cell biologists in general because their topic is too specialized (e.g. infectious microbes, protozoology) are recommended to send them to more relevant journals. Papers reporting whole animal studies or work more suited to a medical journal, e.g. histopathological studies or clinical immunology, are unlikely to be accepted, unless they are fully focused on some important cellular aspect. These last remarks extend particularly to papers on cancer. Unless firmly based on some deeper cellular or molecular biological principle, papers that are highly specialized in this field, with limited appeal to cell biologists at large, should be directed towards journals devoted to cancer, there being very many from which to choose.
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