葛根素通过拮抗TLR4/MyD88介导的NF-κB p65和JNK/FoxO1激活来抑制巨噬细胞M1极化，从而减轻肾脏炎性损伤。
Puerarin suppresses macrophage M1 polarization to alleviate renal inflammatory injury through antagonizing TLR4/MyD88-mediated NF-κB p65 and JNK/FoxO1 activation.
作者信息
Hu Zujian, Chen Dong, Yan Penghua, Zheng Fan, Zhu Hengyue, Yuan Ziwei, Yang Xuejia, Zuo Yidan, Chen Chaosheng, Lu Hong, Wu Lianfeng, Lyu Jianxin, Bai Yongheng
机构信息
Zhejiang Key Laboratory of Intelligent Cancer Biomarker Discovery and Translation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, PR China.
Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China.
出版信息
Phytomedicine. 2024 Sep;132:155813. doi: 10.1016/j.phymed.2024.155813. Epub 2024 Jun 8.
BACKGROUND
Acute kidney injury (AKI) is a clinically common and serious renal dysfunction, characterized by inflammation and damage to tubular epithelial cells. Puerarin, an isoflavone derivative isolated from Pueraria lobata, has been proven to possess exceptional effectiveness in reducing inflammation. However, the effects and underlying mechanisms of puerarin on AKI remain uncertain.
PURPOSE
This study investigated the possible therapeutic effects of puerarin on AKI and explored its underlying mechanism.
STUDY DESIGN AND METHODS
The effects of puerarin on AKI and macrophage polarization were investigated in lipopolysaccharide (LPS)-induced or unilateral ureteral obstruction (UUO)-induced mouse models in vivo and LPS-treated macrophages (Raw264.7) in vitro. Additionally, the effects of puerarin on inflammation-related signaling pathways were analyzed.
RESULTS
Administration of puerarin effectively alleviated kidney dysfunction and reduced inflammatory response in LPS-induced and UUO-induced AKI. In vitro, puerarin treatment inhibited the polarization of M1 macrophages and the release of inflammatory factors in Raw264.7 cells stimulated by LPS. Mechanistically, puerarin downregulated the activities of NF-κB p65 and JNK/FoxO1 signaling pathways. The application of SRT1460 to activate FoxO1 or anisomycin to activate JNK eliminated puerarin-mediated inhibition of JNK/FoxO1 signaling, leading to suppression of macrophage M1 polarization and reduction of inflammatory factors. Further studies showed that puerarin bound to Toll/interleukin-1 receptor (TIR) domain of MyD88 protein, hindering its binding with TLR4, ultimately resulting in downstream NF-κB p65 and JNK/FoxO1 signaling inactivation.
CONCLUSIONS
Puerarin antagonizes NF-κB p65 and JNK/FoxO1 activation via TLR4/MyD88 pathway, thereby suppressing macrophage polarization towards M1 phenotype and alleviating renal inflammatory damage.
背景
急性肾损伤（AKI）是一种临床常见且严重的肾功能障碍，其特征为肾小管上皮细胞的炎症和损伤。葛根素是从野葛中分离出的一种异黄酮衍生物，已被证明在减轻炎症方面具有卓越疗效。然而，葛根素对急性肾损伤的影响及潜在机制仍不明确。
目的
本研究探讨葛根素对急性肾损伤的可能治疗作用，并探究其潜在机制。
研究设计与方法
在体内脂多糖（LPS）诱导或单侧输尿管梗阻（UUO）诱导的小鼠模型以及体外LPS处理的巨噬细胞（Raw264.7）中研究葛根素对急性肾损伤和巨噬细胞极化的影响。此外，分析了葛根素对炎症相关信号通路的影响。
结果
给予葛根素可有效缓解LPS诱导和UUO诱导的急性肾损伤中的肾功能障碍并减轻炎症反应。在体外，葛根素处理可抑制LPS刺激的Raw264.7细胞中M1巨噬细胞的极化和炎症因子的释放。机制上，葛根素下调了NF-κB p65和JNK/FoxO1信号通路的活性。应用SRT1460激活FoxO1或茴香霉素激活JNK消除了葛根素介导的对JNK/FoxO1信号的抑制，导致巨噬细胞M1极化受到抑制且炎症因子减少。进一步研究表明，葛根素与MyD88蛋白的Toll/白细胞介素-1受体（TIR）结构域结合，阻碍其与TLR4结合，最终导致下游NF-κB p65和JNK/FoxO1信号失活。
结论
葛根素通过TLR4/MyD88途径拮抗NF-κB p65和JNK/FoxO1的激活，从而抑制巨噬细胞向M1表型极化并减轻肾脏炎症损伤。
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