OBJECTIVE: This study investigated the possible therapeutic effects of puerarin on AKI and explored its underlying mechanism.
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.
目的:本研究探讨葛根素对AKI可能的治疗作用及其机制。
方法:在脂多糖(LPS)诱导或单侧输尿管梗阻(UUO)诱导的小鼠体内模型和LPS处理的巨噬细胞(Raw264.7)中研究了葛根素对AKI和巨噬细胞极化的影响。此外,分析葛根素对炎症相关信号通路的影响。
结果:服用葛根素可有效减轻LPS诱导和UUO诱导的AKI中的肾功能障碍和炎症反应。体外,葛根素对LPS刺激的Raw264.7细胞内M1巨噬细胞极化和炎症因子释放有抑制作用。机械上,葛根素下调NF-κBp65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JNK/FoxO1信号传导抑制,导致抑制巨噬细胞M1极化和减少炎症因子。进一步研究表明,葛根素与MyD88蛋白的Toll/白介素-1受体(TIR)结构域结合,阻碍其与TLR4的结合,最终导致下游NF-κBp65和JNK/FoxO1信号失活。
结论:葛根素通过TLR4/MyD88通路拮抗NF-κBp65和JNK/FoxO1激活,从而抑制巨噬细胞向M1表型的极化并减轻肾脏炎症损伤。