Aix Marseille University, INSERM, INRA, C2VN, 13005 Marseille, France.
LPNSA, Département de Biologie, Université d'Oran 1 Ahmed Benbella, 31000 Oran, Algérie.
Toxins (Basel). 2018 Oct 12;10(10):412. doi: 10.3390/toxins10100412.
Patients with chronic kidney disease (CKD) display an elevated risk of thrombosis. Thrombosis occurs in cardiovascular events, such as venous thromboembolism, stroke, and acute coronary syndrome, and is a cause of hemodialysis vascular access dysfunction. CKD leads to the accumulation of uremic toxins, which exerts toxic effects on blood and the vessel wall. Some uremic toxins result from tryptophan metabolization in the gut through the indolic and the kynurenine pathways. An increasing number of studies are highlighting the link between such uremic toxins and thrombosis in CKD. In this review, we describe the thrombotic mechanisms induced by tryptophan-derived uremic toxins (TDUT). These mechanisms include an increase in plasma levels of procoagulant factors, induction of platelet hyperactivity, induction of endothelial dysfunction/ impairment of endothelial healing, decrease in nitric oxide (NO) bioavailability, and production of procoagulant microparticles. We focus on one important prothrombotic mechanism: The induction of tissue factor (TF), the initiator of the extrinsic pathway of the blood coagulation. This induction occurs via a new pathway, dependent on the transcription factor Aryl hydrocarbon receptor (AhR), the receptor of TDUT in cells. A better understanding of the prothrombotic mechanisms of uremic toxins could help to find novel therapeutic targets to prevent thrombosis in CKD.
患有慢性肾病 (CKD) 的患者血栓形成风险增加。血栓形成发生在心血管事件中，如静脉血栓栓塞、中风和急性冠状动脉综合征，是血液透析血管通路功能障碍的原因。CKD 导致尿毒素的积累，这些毒素对血液和血管壁产生毒性作用。一些尿毒素来源于肠道中色氨酸通过吲哚和犬尿氨酸途径的代谢。越来越多的研究强调了 CKD 中这些尿毒素与血栓形成之间的联系。在这篇综述中，我们描述了色氨酸衍生的尿毒素 (TDUT) 引起的血栓形成机制。这些机制包括促凝因子血浆水平升高、血小板活性增加、内皮功能障碍/内皮愈合受损、一氧化氮 (NO) 生物利用度降低和促凝微粒体的产生。我们重点介绍一个重要的促血栓形成机制：组织因子 (TF) 的诱导，血液凝固外源性途径的启动子。这种诱导通过一种新的途径发生，该途径依赖于转录因子芳烃受体 (AhR)，即细胞中 TDUT 的受体。更好地了解尿毒素的促血栓形成机制可能有助于找到预防 CKD 中血栓形成的新治疗靶点。
