Abstract
Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-β-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a “dioxin-like” effect.
Highlights
Patients with chronic kidney disease (CKD) are at high risk for cardiovascular diseases
Two other metabolic pathways of tryptophan metabolism are described: the serotonin pathway that leads to melatonin, and the indolic pathway that leads to indolic components such as indoxyl sulfate (IS), indole acetic acid (IAA), and indoxyl-β-D glucuronide (IDG) (Figure 1) [7,11,12]
Using microarray analyses of endothelial cells, we found that IS and IAA induce an upregulation of eight genes regulated by Aryl Hydrocarbon Receptor (AhR), including CYP1A1 and CYP1B1 [30]
Summary
Patients with chronic kidney disease (CKD) are at high risk for cardiovascular diseases. The uremic environment itself is harmful and uremic toxins have emerged as a key factor to explain cardiovascular disease [4] These uremic toxins are classified in three groups by their behavior during dialysis [5]: the small water-soluble molecules, the middle molecules, and the protein-bound molecules, which are hardly removed by conventional hemodialysis treatments. Among uremic toxins, those derived from tryptophan are of particular interest because they have cardiovascular toxicity and they are Aryl Hydrocarbon Receptor (AhR) ligands [6,7]. This paper reviews how toxins derived from tryptophan can play a role in cardiovascular diseases associated with CKD via their property of AhR activation
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