Uremic Solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Thrombosis after Vascular Injury in Humans
| العنوان: | Uremic Solute-Aryl Hydrocarbon Receptor-Tissue Factor Axis Associates with Thrombosis after Vascular Injury in Humans |
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| المؤلفون: | Sowmya Shivanna, Mostafa Belghasem, Gary H. Chang, Vipul C. Chitalia, Jean M. Francis, Faisal Alousi, Laura M. Dember, Vijaya B. Kolachalama, C. Michael Gibson, Joshua Walker, Moshe Shashar, Shinobu Matsuura, Keshab Rijal, Katya Ravid |
| المصدر: | Journal of the American Society of Nephrology. 29:1063-1072 |
| بيانات النشر: | Ovid Technologies (Wolters Kluwer Health), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, medicine.medical_specialty, Gastroenterology, Pattern Recognition, Automated, Thromboplastin, 03 medical and health sciences, Tissue factor, chemistry.chemical_compound, Clinical Research, Internal medicine, medicine, Humans, Metabolomics, Myocardial infarction, Renal Insufficiency, Chronic, Kynurenine, Aged, Uremia, Clinical Trials as Topic, biology, business.industry, Thrombosis, General Medicine, Middle Aged, Vascular System Injuries, AV Fistula Thrombosis, medicine.disease, Aryl hydrocarbon receptor, Clopidogrel, 030104 developmental biology, Tryptophan Metabolite, Receptors, Aryl Hydrocarbon, chemistry, Nephrology, biology.protein, Female, business, Indican, Signal Transduction, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1533-3450 1046-6673 |
| DOI: | 10.1681/asn.2017080929 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::93be94690792365c7d114d998ef88219 https://doi.org/10.1681/asn.2017080929 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....93be94690792365c7d114d998ef88219 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15333450 10466673 |
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| DOI: | 10.1681/asn.2017080929 |