Embelin attenuates lipopolysaccharide-induced acute kidney injury through the inhibition of M1 macrophage activation and NF-κB signaling in mice.

Embelin 通过抑制 M1 巨噬细胞活化和 NF - κ B 信号减轻小鼠脂多糖诱导的急性肾损伤。

• 影响指数: 3.776
• 发表时间: Mar 2023
• 来源期刊: Heliyon
• DOI: 10.1016/j.heliyon.2023.e14006
• PMID: 36938407
• 文章类型: Journal Article
• 作者列表: Tang Q,Tang Y,Yang Q,Chen R,Zhang H,Luo H,Xiao Q,Liu K,Huang L,Chen J,Wang L,Song X,Chen S,Li G,Wang L,Li Y

关键词: AKI, acute kidney injury; BMDMs, bone marrow-derived macrophages; BUN, blood urea nitrogen; DMEM, Dulbecco's modified eagle's medium; Embelin; FBS, fetal bovine serum; HE, hematoxylin & eosin; ICU, intensive care unit; IHC, immunohistochemistry; Inflammation; LPS, lipopolysaccharide; Macrophage; PAS, periodic-acid Schiff; Phosphorylated NF-κB p65 translocation; Scr, serum creatinine; Septic acute kidney injury; mIF, multiplex immunofluorescent

Abstract

Septic acute kidney injury (AKI) is commonly associated with renal dysfunction and high mortality in patients. Owing to the rapid and violent occurrence of septic AKI with inflammation, there are no effective therapies to clinically treat it. Embelin, a natural product, has a potential regulatory role in immunocytes. However, the role and mechanism of embelin in septic AKI remains unknown. This study aimed to elucidate the role of embelin in macrophage regulation in lipopolysaccharide (LPS)-induced septic AKI. Embelin was intraperitoneally administered to mice after LPS injection. And bone marrow-derived macrophages (BMDMs) were subsequently isolated from the mice to explore the immunomodulatory role of embelin in macrophages. We found that embelin attenuated renal dysfunction and pathological renal damage in the LPS-induced sepsis mouse model. Molecular docking predicted that embelin could bind to phosphorylated NF-κB p65 at the ser536 site. Embelin inhibited the translocation of NF-κB p65 via phosphorylation at ser536 in LPS-induced AKI. It also reduced the secretion of IL-1β and IL-6 and increased the secretion of IL-10 and Arg-1 of BMDMs and mice after LPS stimulation, indicating that embelin suppressed macrophage M1 activation in LPS-induced AKI. Therefore, embelin attenuated LPS-induced septic AKI by suppressing NF-κB p65 at ser536 in activated macrophages. This study preclinically suggests a therapeutic role of embelin in septic AKI.

摘要

脓毒症急性肾损伤（AKI）通常与患者的肾功能不全和高死亡率有关。由于感染性AKI伴有炎症的快速和暴力发生，临床上没有有效的治疗方法。恩贝林,一种天然产物,在免疫细胞中具有潜在的调节作用。然而,Enbelin在脓毒性AKI中的作用和机制尚不清楚。本研究旨在阐明Enbelin在脂多糖（LPS）诱导的脓毒症AKI中巨噬细胞调节中的作用。LPS注射后，将Embelin腹膜内给予小鼠。随后从小鼠中分离出骨髓来源的巨噬细胞（BMDMs），以探索embelin在巨噬细胞中的免疫调节作用。我们发现，在LPS诱导的脓毒症小鼠模型中，恩贝林减轻了肾功能障碍和病理性肾损害。分子对接预测embelin可以在ser536位点与磷酸化的NF-κBp65结合。Embelin通过在LPS诱导的AKI中ser536处的磷酸化抑制NF-κBp65的易位。LPS刺激后，BMDMs和小鼠IL-1β和IL-6的分泌减少，IL-10和Arg-1的分泌增加，提示恩贝林抑制LPS诱导的AKI中巨噬细胞M1的活化。因此,embelin通过抑制活化巨噬细胞中ser536处的NF-κBp65来减轻LPS诱导的感染性AKI。这项临床前研究表明，embelin在脓毒性AKI中具有治疗作用。