Abstract
Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)—derived from tryptophan metabolism—accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients.
Highlights
Endothelium was historically described as a “cellophane type” barrier that separated blood from other organs and tissues
In response to an injury, the endothelium is activated resulting in a pro-inflammatory and procoagulant state with an abnormal vascular tone
indoxyl sulfate (IS) induces oxygen species production activation of the NADPH oxidase (NOX) in mitochondria and plasma membrane. All these pathways converge to increase the production of proteins involved in inflammation, thrombosis and leukocyte adhesion: tissue factor (TF), intercellular adherence protein (ICAM-1), membrane cofactor protein 1 (MCP1), E-selectin and interleukin 8 (Il-8)
Summary
Endothelium was historically described as a “cellophane type” barrier that separated blood from other organs and tissues. Despite the selective permeable interface separating vascular and interstitial compartment, several functions were described over the past 40 years. The endothelium is a dramatic regulator of hemostasis, inflammation and vascular tone in collaboration with vascular smooth muscle cells (vSMC), via a nitric oxide (NO)-dependent pathway [1,2]. The endothelium plays an important role in controlling leukocyte trafficking, metabolism, vascular permeability and angiogenesis (Figure 1). Endothelial cells cover the whole cardiovascular system surface. Endothelial cell characteristics are different, depending on the type of vessel (microvessel vs macrovessels) or organ. Endothelial cells insure an antithrombotic and anti-inflammatory environment to the vessels and provide oxygen and nutrients to all tissues.
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