The Aryl Hydrocarbon Receptor-Activating Effect of Uremic Toxins from Tryptophan Metabolism: A New Concept to Understand Cardiovascular Complications of Chronic Kidney Disease

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.

Associations of Plasma Kynurenines With Risk of Acute Myocardial Infarction in Patients With Stable Angina Pectoris

“…20 This metabolite and other kynurenines were also identified as endogenous ligands of the transcription factor aryl hydrocarbon receptor known to mediate vascular inflammation and procoagulant effects. 21 Our findings of positive correlations of kynurenines to creatinine are in line with previous publications and possibly reflect the combination of increased synthesis because of inflammatory activation 22 and reduced renal clearance 23 in patients with chronic kidney disease. Indeed, Trp metabolism has been hypothesized as a causal mechanism contributing to accelerated atherosclerosis in renal disease.…”

“…Indeed, Trp metabolism has been hypothesized as a causal mechanism contributing to accelerated atherosclerosis in renal disease. 21,24 Notably, however, adjustment for serum creatinine levels had only minor effects on our risk estimates. Hence, the associations of kynurenines with outcomes seem not solely to reflect pathways activated in renal dysfunction.…”

Association of Height with Mortality in Patients Undergoing Maintenance Hemodialysis

“…If this were the case, then taller people, who again for the same weight should have greater lean body mass, might be at greater risk for certain water-soluble uremic toxins. Some uremic toxins may have apoptotic, inflammatory, oxidative, or coagulative effects on the cardiovascular system and other organ systems (27,28), and are directly associated with cardiovascular morbidity and mortality in the CKD population (27,29,30). Aortic atherosclerosis with calcification is commonly associated with increased aortic pulse wave velocity after cardiac systole (31).…”

Reduced Glutamatergic Neurotransmission as Possible Indicator of Unfavorable Prognosis

“…[69] Its content in patients with uremia exceeds the reference values by many times and correlates with the development of uremic symptoms. Toxic effects of the relevant concentrations of KYNA have been confirmed by experimental studies.…”