title: The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia.
abstract: Patients with CKD suffer high rates of thrombosis, particularly after endovascular interventions, yet few options are available to improve management and reduce thrombotic risk. We recently demonstrated that indoxyl sulfate (IS) is a potent CKD-specific prothrombotic metabolite that induces tissue factor (TF) in vascular smooth muscle cells (vSMCs), although the precise mechanism and treatment implications remain unclear. Because IS is an agonist of the aryl hydrocarbon receptor (AHR), we first examined the relationship between IS levels and AHR-inducing activity in sera of patients with ESRD. IS levels correlated significantly with both vSMC AHR activity and TF activity. Mechanistically, we demonstrated that IS activates the AHR pathway in primary human aortic vSMCs, and further, that AHR interacts directly with and stabilizes functional TF. Antagonists directly targeting AHR enhanced TF ubiquitination and degradation and suppressed thrombosis in a postinterventional model of CKD and endovascular injury. Furthermore, AHR antagonists inhibited TF in a manner dependent on circulating IS levels. In conclusion, we demonstrated that IS regulates TF stability through AHR signaling and uncovered AHR as an antithrombotic target and AHR antagonists as a novel class of antithrombotics. Together, IS and AHR have potential as uremia-specific biomarkers and targets that may be leveraged as a promising theranostic platform to better manage the elevated thrombosis rates in patients with CKD.
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;
authors.forename: Sowmya
authors.initials: S
authors.lastname: Shivanna
authors.affiliation: Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts;
authors.forename: Kumaran
authors.initials: K
authors.lastname: Kolandaivelu
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;
authors.forename: Moshe
authors.initials: M
authors.lastname: Shashar
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts;
authors.forename: Mostafa
authors.initials: M
authors.lastname: Belghasim
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;
authors.forename: Laith
authors.initials: L
authors.lastname: Al-Rabadi
authors.affiliation: Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts; Biological Engineering Department, Institut Químic de Sarrià, Ramon Llull University, Barcelona, Spain;
authors.forename: Mercedes
authors.initials: M
authors.lastname: Balcells
authors.affiliation: Metabolomics Core, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;
authors.forename: Anqi
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts;
authors.forename: Janice
authors.initials: J
authors.lastname: Weinberg
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts;
authors.forename: Jean
authors.initials: J
authors.lastname: Francis
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts; and.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Pollastri
authors.affiliation: Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts;
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
authors.affiliation: Department of Environmental Health, Boston University School of Public Health, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherr
authors.affiliation: Renal Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; vichital@bu.edu.
authors.forename: Vipul C
authors.initials: VC
authors.lastname: Chitalia
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D007200:Indican / Q000502:physiology; D008297:Male; D008875:Middle Aged; D055550:Protein Stability; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors / Q000502:physiology*; D013925:Thromboplastin / Q000502:physiology*; D013927:Thrombosis / Q000209:etiology* / Q000517:prevention & control*; D014511:Uremia / Q000150:complications*
chemical_list: D018336:Receptors, Aryl Hydrocarbon; D013925:Thromboplastin; D007200:Indican
keywords: CKD; thrombosis; uremia