Iwashima Tomomi, Takemura Yui, Kishimoto Yoshimi, Ono Chihiro, Watanabe Ayano, Iida Kaoruko
Department of Food and Nutritional Sciences, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.
Department of Food Science and Human Nutrition, Setsunan University, Osaka, Japan.
Food Nutr Res. 2024 Jul 31;68. doi: 10.29219/fnr.v68.10032. eCollection 2024.
Uremic toxin indoxyl sulfate (IS) induces vascular inflammation, a crucial event in renal failure, and vascular complications in patients with chronic kidney disease (CKD). In endothelial cells, IS increases the production of inflammatory cytokines partially via the activation of the aryl hydrocarbon receptor (AhR), and several food flavonoids have been reported to act as antagonists of AhR.
This study aimed to investigate whether antagonistic flavonoids can attenuate IS-induced inflammatory responses in vascular endothelial cells and renal failure .
Human umbilical vein endothelial cells (HUVECs) pretreated with the flavones apigenin, chrysin, or luteolin were stimulated with IS. Expression levels of genes involved in AhR signaling, inflammatory cytokine production, and reactive oxygen species (ROS) production were analyzed. Uninephrectomized mice were orally administered chrysin and received daily intraperitoneal injections of IS for 4 weeks.
In HUVECs, IS upregulated the mRNA expression of AhR-targeted genes ( and ), and genes involved in inflammation (, , and ) and monocyte invasion/adhesion (). All three flavones attenuated the IS-induced increase in the expression of these mRNAs. They also suppressed the IS-induced nuclear translocation of AhR and intracellular ROS production. Furthermore, IS-induced phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was inhibited by treatment with these flavones. The results of experiments showed that administration with chrysin attenuated the elevation of blood urea nitrogen levels and AhR-target gene expression and the pathological impairment of renal tissues in mice, regardless of higher serum levels of IS.
Natural food flavones antagonizing AhR exerted protective effects against IS-induced inflammation through the inhibition of the AhR-STAT3 pathway in HUVECs. Moreover, chrysin ameliorated IS-induced renal dysfunction in a mouse model of CKD. These flavonoids could be a therapeutic strategy for vascular inflammation in CKD.
尿毒症毒素硫酸吲哚酚（IS）可引发血管炎症，这是肾衰竭的关键事件，也是慢性肾脏病（CKD）患者血管并发症的重要因素。在内皮细胞中，IS部分通过激活芳烃受体（AhR）增加炎症细胞因子的产生，并且有报道称几种食物中的黄酮类化合物可作为AhR的拮抗剂。
本研究旨在探究具有拮抗作用的黄酮类化合物是否能减轻IS诱导的血管内皮细胞炎症反应及肾衰竭。
用黄酮类化合物芹菜素、白杨素或木犀草素预处理人脐静脉内皮细胞（HUVECs），然后用IS刺激。分析参与AhR信号传导、炎症细胞因子产生和活性氧（ROS）产生的基因表达水平。对单侧肾切除的小鼠口服给予白杨素，并每天腹腔注射IS，持续4周。
在HUVECs中，IS上调了AhR靶向基因（和）以及参与炎症（、、和）和单核细胞侵袭/黏附（）的基因的mRNA表达。所有三种黄酮均减弱了IS诱导的这些mRNA表达的增加。它们还抑制了IS诱导的AhR核转位和细胞内ROS产生。此外，这些黄酮处理可抑制IS诱导的信号转导和转录激活因子3（STAT3）的磷酸化。实验结果表明，无论血清IS水平较高，给予白杨素均可减轻小鼠血尿素氮水平的升高、AhR靶向基因表达及肾组织的病理损伤。
拮抗AhR的天然食物黄酮通过抑制HUVECs中的AhR-STAT3途径对IS诱导的炎症发挥保护作用。此外，白杨素改善了CKD小鼠模型中IS诱导的肾功能障碍。这些黄酮类化合物可能是治疗CKD血管炎症的一种策略。
