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Uremic Solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Thrombosis after Vascular Injury in Humans

芳香烃受体 血栓形成 医学 内科学 犬尿氨酸途径 犬尿氨酸 肾功能 血小板活化 血小板 药理学 化学 生物化学 色氨酸 转录因子 基因 氨基酸
作者
Vijaya B. Kolachalama,Moshe Shashar,Faisal Alousi,Sowmya Shivanna,Keshab Rijal,Mostafa Belghasem,Joshua Walker,Shinobu Matsuura,Gary H. Chang,C. Michael Gibson,Laura M. Dember,Jean Francis,Katya Ravid,Vipul C. Chitalia
出处
期刊:Journal of The American Society of Nephrology 卷期号:29 (3): 1063-1072 被引量:88
标识
DOI:10.1681/asn.2017080929
摘要

Individuals with CKD are particularly predisposed to thrombosis after vascular injury. Using mouse models, we recently described indoxyl sulfate, a tryptophan metabolite retained in CKD and an activator of tissue factor (TF) through aryl hydrocarbon receptor (AHR) signaling, as an inducer of thrombosis across the CKD spectrum. However, the translation of findings from animal models to humans is often challenging. Here, we investigated the uremic solute–AHR–TF thrombosis axis in two human cohorts, using a targeted metabolomics approach to probe a set of tryptophan products and high-throughput assays to measure AHR and TF activity. Analysis of baseline serum samples was performed from 473 participants with advanced CKD from the Dialysis Access Consortium Clopidogrel Prevention of Early AV Fistula Thrombosis trial. Participants with subsequent arteriovenous thrombosis had significantly higher levels of indoxyl sulfate and kynurenine, another uremic solute, and greater activity of AHR and TF, than those without thrombosis. Pattern recognition analysis using the components of the thrombosis axis facilitated clustering of the thrombotic and nonthrombotic groups. We further validated these findings using 377 baseline samples from participants in the Thrombolysis in Myocardial Infarction II trial, many of whom had CKD stage 2–3. Mechanistic probing revealed that kynurenine enhances thrombosis after vascular injury in an animal model and regulates thrombosis in an AHR-dependent manner. This human validation of the solute-AHR-TF axis supports further studies probing its utility in risk stratification of patients with CKD and exploring its role in other diseases with heightened risk of thrombosis.
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