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Aryl Hydrocarbon Receptor Activation and Tissue Factor Induction by Fluid Shear Stress and Indoxyl Sulfate in Endothelial Cells

Authors
  • Lano, Guillaume1
  • Laforêt, Manon1
  • Von Kotze, Clarissa
  • Perrin, Justine
  • Addi, Tawfik1, 2
  • Brunet, Philippe1,
  • Poitevin, Stéphane1
  • Burtey, Stéphane1,
  • Dou, Laetitia1
  • 1 (S.B.)
  • 2 Département de Biologie, Université d’Oran 1 Ahmed Benbella, LPNSA, 31000 Oran, Algerie
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Mar 31, 2020
Volume
21
Issue
7
Identifiers
DOI: 10.3390/ijms21072392
PMID: 32244284
PMCID: PMC7178278
Source
PubMed Central
Keywords
License
Green

Abstract

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 PTGS2 (encoding for COX2), AHRR , CYP1A1 , and CYP1B1 , as well as F3 (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.

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