Indoxyl Sulfate Induces IL-6 Expression in Vascular Endothelial and Smooth Muscle Cells through OAT3-Mediated Uptake and Activation of AhR/NF-κB Pathway
Indoxyl Sulfate Induces IL-6 Expression in Vascular Endothelial and Smooth Muscle Cells through OAT3-Mediated Uptake and Activation of AhR/NF-κB Pathway
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DOI：
10.1159/000365217
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发表时间：
2014-01-01
影响因子：
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通讯作者：
Niwa, Toshimitsu
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文献类型：
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作者：
Adelibieke, Yelixiati;Yisireyili, Maimaiti;Niwa, Toshimitsu
背景/目的：白细胞介素-6 （IL-6）是慢性肾脏疾病（CKD）患者预后预测价值最高的炎症生物标志物之一。本研究旨在探讨硫酸吲哚酚（IS）对血管细胞IL-6表达的影响。方法：给药于正常和高血压大鼠。人脐静脉内皮细胞（HUVECs）和人主动脉平滑肌细胞（HASMCs）在加或不加IS的条件下孵育。结果：免疫组化显示is给药大鼠主动脉组织中IL-6表达升高。IS在huvec和HASMCs中以时间和剂量依赖的方式增加IL-6的表达。使用小干扰RNA （siRNA）敲低有机阴离子转运蛋白3 （OAT3）可抑制is诱导的HUVECs和HASMCs中IL-6的表达。IS诱导HUVECs和HASMCs中芳烃受体（AhR）和核因子κ B （nf - κ B）亚基p65的激活。AhR siRNA和p65 siRNA均抑制is诱导的IL-6表达。AhR siRNA抑制is诱导的p65磷酸化和核易位，但不改变p65的总水平。然而，p65 siRNA不抑制is诱导的AhR核易位。因此，AhR负责is诱导的p65信号转导。结论：IS通过OAT3/AhR/NF-kappa B通路诱导血管内皮细胞和平滑肌细胞IL-6表达。(C) 2014 S. Karger AG，巴塞尔
Background/Aims: Interleukin-6 (IL-6) is one of the inflammation biomarkers with highest predictive value for outcome in chronic kidney disease (CKD) patients. The present study aimed to determine the effects of indoxyl sulfate (IS) on IL-6 expression in vascular cells. Methods: IS was administered to normo- and hypertensive rats. Human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HASMCs) were incubated with or without IS. Results: Immunohistochemistry revealed that IS-administered rats showed increased expression of IL-6 in the aortic tissues. IS increased IL-6 expression in HUVECs and HASMCs in a time-and dose-dependent manner. Knockdown of organic anion transporter 3 (OAT3) using small interfering RNA (siRNA) inhibited IS-induced expression of IL-6 in HUVECs and HASMCs. IS induced activation of aryl hydrocarbon receptor (AhR) and nuclear factor-kappa B (NF-kappa B) subunit p65 in HUVECs and HASMCs. Both AhR siRNA and p65 siRNA inhibited IS-induced expression of IL-6. AhR siRNA inhibited IS-induced phosphorylation and nuclear translocation of p65 without change in total p65 level. However, p65 siRNA did not inhibit IS-induced nuclear translocation of AhR. Thus, AhR is responsible for IS-induced p65 signaling transduction. Conclusion: IS induces IL-6 expression in vascular endothelial and smooth muscle cells through OAT3/AhR/NF-kappa B pathway. (C) 2014 S. Karger AG, Basel