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.
Highlights
Chronic kidney disease (CKD) leads to a pathological accumulation of uremic toxins from tryptophan metabolism, such as indoxyl sulfate (IS), indole-3 acetic acid (IAA), and kynurenine [1]
We first studied the mRNA expression of aryl hydrocarbon receptor (AHR) and of its repressor AHR repressor (AHRR) in human umbilical vein endothelial cells (HUVEC) exposed for 4 h and 24 h to laminar shear stress of 5 dynes/cm2 and/or to the AHR agonist IS at 200 μM
Depending on the cell type and AHR agonist, COX2 can be regulated via the genomic and the non-genomic pathways of AHR activation [9–11]
Summary
Chronic kidney disease (CKD) leads to a pathological accumulation of uremic toxins from tryptophan metabolism, such as indoxyl sulfate (IS), indole-3 acetic acid (IAA), and kynurenine [1]. These toxins are agonists of the transcription factor aryl hydrocarbon receptor (AHR) [1–3] and induce its activation in different cells, notably endothelial cells [1,4]. The accumulation of AHR agonists in CKD patients is deleterious [4,5], and many of the harmful effects of tryptophan-derived uremic toxins are related to their AHR-activating ability [1,4]. AHR translocates to the nucleus where it forms a heterodimer with the aryl hydrocarbon nuclear translocator (ARNT), which recruits additional transcriptional cofactors [6]. COX2 regulation via AHR is somewhat different, because COX2 can be regulated via both the genomic and the non-genomic pathways of AHR activation, depending on the cell type and AHR agonist [9–11]
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