Indoxyl Sulfate, a Uremic Endotheliotoxin

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.

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease

“…After binding the receptor to the ligand, the complex is shifted to the cell nucleus and dimerized with the aryl hydrocarbon receptor nuclear translocator (ARNT) protein, which allows transcription of a number of genes. It has also been described that-in the positive feedback mechanism-activation of the aromatic hydrocarbon receptor (AhR) by uremic toxins exacerbates chronic inflammation and the production of ROS in endothelial cells, vascular smooth muscle cells, and leukocytes [132].…”

“…In patients with CKD, the accumulation of products of both the kynurenine pathway and the indole pathway correlates with markers of atherosclerotic organ damage, such as the presence of coronary disease [130], the carotid intima-media thickness (IMT) [189], ankle-brachial index [190], and echocardiographic markers of left ventricular diastolic failure [190]. Activation of the aromatic hydrocarbon receptor (AhR) by tryptophan metabolites has been proven to promote the osteoblastic transformation of VSMC, increase the expression of adhesion molecules (VCAM-1, ICAM-1), as well as disrupt endothelial cell function and endothelial nitric oxide production [132,191]. Oxidative stress also affects the accumulation of protein-related uremic toxins.…”

Indoxyl Sulfate-Mediated Metabolic Alteration of Transcriptome Signatures in Monocytes of Patients with End-Stage Renal Disease (ESRD)

“…Thus, this suggests that these changes are potentially attributable to the chronic exposure to uremic toxins. IS and PCS, which originate from dietary amino acid metabolites of colonic microbial organisms, are the two most problematic uremic toxins, conferring renal and cardiovascular toxicity by increased inflammation, calcification, and oxidative stress [ 11 , 23 , 24 , 25 ]. To explore uremic toxin-related changes in gene expression in ESRD patient-derived monocytes, purified monocytes from healthy controls were treated with IS or PCS for 24 h followed by microarray analysis of these samples.…”

“…Cardiovascular disease (CVD) is a highly common complication and the major cause of death in patients with end-stage renal disease (ESRD) [ 6 ]. Several mechanisms have been proposed for the heightened risk for CVD in CKD, including infiltration of monocytes into arteries, increased cytokine production, and endothelial dysfunction [ 15 , 23 ]. Among over 100 uremic toxins identified, IS and PCS have been extensively investigated as the main uremic toxins involved in the progression of CVD [ 27 , 28 , 29 ].…”

“…Moreover, both play a pivotal role in the pathogenesis of CVD through endothelial dysfunction, recruitment of leukocytes due to increased adhesion molecules such as VCAM-1, and reactive oxygen species (ROS) production [ 31 , 32 ]. The majority of studies have focused primarily on the adverse effects of IS and PCS on renal tissue, endothelial cells, and skeletal muscle cells [ 14 , 23 , 33 ]. Despite a key role of monocytes in the pathogenesis of CVD, the impact of IS and PCS on immune cells in patients with CKD remains elusive [ 13 , 16 , 17 , 34 ].…”