Yan Ying, Tan Rui-Zhi, Liu Peng, Li Jian-Chun, Zhong Xia, Liao Yuan, Lin Xiao, Wei Cong, Wang Li
Research Center of Combine Traditional Chinese and Western Medicine, Affiliated Traditional Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China (mainland).
Shunyi Branch, Beijing Hospital of Traditional Chinese Medicine, Beijing, China (mainland).
Med Sci Monit. 2020 May 4;26:e921114. doi: 10.12659/MSM.921114.
BACKGROUND Acute kidney injury (AKI) is one of the most common complications in clinic, but there is still no effective treatment. Oridonin, extracted from Rabdosia rubescens, has been identified to promote inhibitory effects on tumor, inflammatory and fibrosis by previous study. This study aimed to assess the kidney-protective role of Oridonin in AKI and the underlying mechanism by which Oridonin improves AKI in vivo and inhibits inflammation in LPS-induced bone marrow-derived macrophages (BMDM) in vitro. MATERIAL AND METHODS SPF C57BL/6J male mice (8 - 10 weeks old, body weight 20 - 25 g) were divided into 3 groups - sham group, AKI group, and Oridonin-treated AKI group - with 6 mice in each group. In the in vitro study, LPS-induced inflammatory BMDM cells were treated with Oridonin and agonist of AKT. The expression and secretion levels of inflammation-related indicators and AKT-related signaling molecules were detected by real-time PCR, ELISA, Western blot, and immunofluorescence. Also, various methods are used to assess renal function and pathological changes. RESULTS The results showed that Oridonin treatment significantly improved the serum creatinine and BUN levels in AKI mice. Interestingly, treatment with Oridonin also resulted in decreased the infiltration of macrophages in renal tissues of AKI mice, which was associated with decreased expression and activation of AKT and its related signaling pathways, such as NF-kappaB and STAT3, suggesting that Oridonin attenuates AKI kidney injury via a mechanism associated with reducing the inflammatory response of macrophages in the AKI kidney. This was investigated in vitro in macrophages, and the results showed that Oridonin reduced the LPS-stimulated inflammatory response in macrophages. Mechanistically, the addition of Oridonin reversed LPS-induced downregulation of AKT, NF-kappaB, and STAT3 expression and inflammatory response in macrophages, suggesting that Oridonin has a protective role, via the AKT-related signaling pathways, in reducing the inflammatory response of macrophages in AKI mice. This was further confirmed by adding agonist of AKT of IGF-1 to block the inhibitory effect of Oridonin on inflammatory response in vitro. CONCLUSIONS Oridonin ameliorates AKI kidney injuries by suppressing AKT-mediated inflammatory response of macrophages.
背景 急性肾损伤（AKI）是临床上最常见的并发症之一，但仍没有有效的治疗方法。先前的研究已证实，从冬凌草中提取的冬凌草素对肿瘤、炎症和纤维化具有抑制作用。本研究旨在评估冬凌草素在AKI中的肾脏保护作用，以及其在体内改善AKI和体外抑制脂多糖诱导的骨髓来源巨噬细胞（BMDM）炎症的潜在机制。 材料与方法 将SPF级C57BL/6J雄性小鼠（8 - 10周龄，体重20 - 25 g）分为3组——假手术组、AKI组和冬凌草素治疗的AKI组，每组6只小鼠。在体外研究中，用冬凌草素和AKT激动剂处理脂多糖诱导的炎性BMDM细胞。通过实时PCR、ELISA、蛋白质免疫印迹法和免疫荧光法检测炎症相关指标和AKT相关信号分子的表达及分泌水平。此外，采用多种方法评估肾功能和病理变化。 结果 结果显示，冬凌草素治疗显著改善了AKI小鼠的血清肌酐和尿素氮水平。有趣的是，冬凌草素治疗还导致AKI小鼠肾组织中巨噬细胞浸润减少，这与AKT及其相关信号通路（如核因子κB和信号转导子和转录激活子3）的表达和激活减少有关，表明冬凌草素通过与减少AKI肾脏中巨噬细胞炎症反应相关的机制减轻AKI肾损伤。在巨噬细胞中进行的体外研究对此进行了验证，结果表明冬凌草素降低了脂多糖刺激的巨噬细胞炎症反应。从机制上讲，添加冬凌草素可逆转脂多糖诱导的巨噬细胞中AKT、核因子κB和信号转导子和转录激活子3表达下调及炎症反应，表明冬凌草素通过AKT相关信号通路对减轻AKI小鼠巨噬细胞炎症反应具有保护作用。在体外添加胰岛素样生长因子 - 1的AKT激动剂以阻断冬凌草素对炎症反应的抑制作用，进一步证实了这一点。 结论 冬凌草素通过抑制AKT介导的巨噬细胞炎症反应改善AKI肾损伤。
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