Aix Marseille Univ, INSERM, INRAE, C2VN, 13005 Marseille, France.
Centre de Néphrologie et Transplantation Rénale, AP-HM, Hôpital de la Conception, 13005 Marseille, France.
Int J Mol Sci. 2020 Mar 31;21(7):2392. doi: 10.3390/ijms21072392.
Endogenous agonists of the transcription factor aryl hydrocarbon receptor (AHR) such as the indolic uremic toxin, indoxyl sulfate (IS), accumulate in patients with chronic kidney disease. AHR activation by indolic toxins has prothrombotic effects on the endothelium, especially via tissue factor (TF) induction. In contrast, physiological AHR activation by laminar shear stress (SS) is atheroprotective. We studied the activation of AHR and the regulation of TF by IS in cultured human umbilical vein endothelial cells subjected to laminar fluid SS (5 dynes/cm2). SS and IS markedly increased the expression of AHR target genes (encoding for COX2), , , and , as well as (encoding for TF), in an AHR-dependent way. IS amplified SS-induced TF mRNA and protein expression and upregulation of AHR target genes. Interestingly, tyrosine kinase inhibition by genistein decreased SS- but not IS-induced TF expression. Finally, the increase in TF expression induced by laminar SS was not associated with increased TF activity. In contrast, IS increased TF activity, even under antithrombotic SS conditions. In conclusion, IS and SS induce AHR activation and AHR-dependent TF upregulation by different mechanisms. Impairment of the antithrombotic properties of shear stressed endothelium by toxic AHR agonists could favor cardiovascular diseases in CKD.
内源性芳香烃受体（AHR）转录因子激动剂，如吲哚类尿毒症毒素吲哚硫酸酯（IS），在慢性肾脏病患者中蓄积。吲哚类毒素通过 AHR 激活可导致内皮的促血栓形成作用，特别是通过组织因子（TF）诱导。相比之下，层流切应力（SS）引起的生理性 AHR 激活具有抗动脉粥样硬化作用。我们研究了 IS 在培养的人脐静脉内皮细胞中经层流 SS（5 达因/平方厘米）处理时对 AHR 及 TF 的调节作用。SS 和 IS 以 AHR 依赖性方式明显增加了 AHR 靶基因（编码 COX2）、、、和的表达，以及 TF（编码 TF）的表达。IS 放大了 SS 诱导的 TF mRNA 和蛋白表达以及 AHR 靶基因的上调。有趣的是，酪氨酸激酶抑制剂金雀异黄素可降低 SS-但不降低 IS-诱导的 TF 表达。最后，层流 SS 诱导的 TF 表达增加与 TF 活性增加无关。相反，即使在抗血栓形成的 SS 条件下，IS 也会增加 TF 活性。总之，IS 和 SS 通过不同的机制诱导 AHR 激活和 AHR 依赖性 TF 上调。有毒 AHR 激动剂损害受切应力作用的内皮的抗血栓形成特性可能会促进 CKD 中的心血管疾病。
