Cardiovascular disease (CVD) is a major complication of chronic kidney disease (CKD), despite improvements in patient care. Vascular inflammation is a crucial process in the pathogenesis of CVD and a critical factor in the cardiovascular complications in CKD patients. CKD promotes a pro-inflammatory environment that impacts the vascular wall, leading to endothelial dysfunction, increased oxidative stress, and vascular remodeling. The uremic toxins that accumulate as kidney function declines are key contributors to vascular inflammatory processes. Our review will examine how CKD leads to vascular inflammation, paving the way to CVD. We will provide an overview of the mechanisms of vascular inflammation induced by uremic toxins, with a particular focus on those derived from tryptophan metabolism. These toxins, along with their receptor, the aryl hydrocarbon receptor (AHR), have emerged as key players linking inflammation and thrombosis. A deeper understanding of the mechanisms underlying inflammation in CKD, particularly those driven by uremic toxins, could reveal valuable therapeutic targets to alleviate the burden of CVD in CKD patients.

Arteriovenous (AV) access complications remain a major cause of morbidity in hemodialysis patients, influenced by multiple factors, including endothelial inflammation induced by uremia. In this study, we investigated the mechanisms underlying the upregulation of endothelial chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by indolic uremic toxins, as well as their association with AV access complications in hemodialysis patients. In cultured human endothelial cells, IL-8 and MCP-1 were upregulated by indolic uremic toxins through activation of their receptor, the aryl hydrocarbon receptor (AHR), and non-canonical TGF-β pathway involving TAK1/p38 MAPK/AP-1 signaling. In a retrospective observational study of 204 hemodialysis patients, baseline serum IL-8 or MCP-1 were positively correlated with indolic uremic toxins and TGFβ1. Additionally, serum IL-8 ≥ 40.26 pg/mL and serum MCP-1 were independently associated with an increased risk of AV access complications over a 2-year period. In conclusion, we demonstrated that indolic uremic toxins promote endothelial inflammation by inducing IL-8 and MCP-1 expression via AHR activation and non-canonical TGF-β signaling. Clinically, elevated serum IL-8 and MCP-1 were independently associated with an increased risk of AV access complications in hemodialysis patients.

Hemodialysis patients exhibit endothelial dysfunction, contributing to elevated cardiovascular risk and complications of the arteriovenous access. These patients have elevated serum levels of myostatin, a member of the transforming growth factor-β (TGFβ) superfamily, and of the uremic toxin indoxyl sulfate, both of which are pro-inflammatory towards endothelial cells. We hypothesized that myostatin and indoxyl sulfate may synergistically induce endothelial dysfunction by impairing endothelial proliferation and promoting a pro-inflammatory phenotype. We first investigated the effect of myostatin on cultured endothelial cells in the presence of indoxyl sulfate. We then examined the association between serum myostatin concentrations and the occurrence of cardiovascular and arteriovenous access complications in hemodialysis patients. In vitro, myostatin exhibited endotheliotoxic effects in the presence of a uremic concentration of indoxyl sulfate, enhanced its antiproliferative effect, and amplified MCP-1 and IL-8 chemokine upregulation. In patients, high myostatin concentrations correlated with indoxyl sulfate concentrations and were associated with an increased risk of arteriovenous access complications. These findings suggest that myostatin amplifies endothelial injury mediated by indolic uremic toxins and might contribute to AV access complications.

Patients with chronic kidney disease (CKD) are exposed to high levels of uremic toxins and have an increased risk of cardiovascular disease. Among these toxins, indolic compounds such as indoxyl sulfate (IS) are predictors of cardiovascular events and mortality in CKD patients and induce a procoagulant and proinflammatory vascular phenotype through activation of the aryl hydrocarbon receptor (AhR). Targeting AhR activation by indolic toxins may therefore help prevent cardiovascular complications in CKD. To this end, we investigated in vitro whether natural dietary AhR ligands (galangin, quercetin, curcumin and indole-3-carbinol) could antagonize IS-induced AhR activation and the associated inflammatory response in endothelial cells. The activation of the AhR genomic pathway was assessed by measuring the expression of AhR target genes (CYP1A1, CYP1B1, and AHRR) in endothelial cells and by evaluating AhR-dependent transcriptional activity using a CALUX-AHRE luciferase reporter assay in HG40/6 cells. In parallel, endothelial inflammation was evaluated by analyzing the expression of AhR-related inflammatory genes: F3/tissue factor, PTGS2/COX-2, CCL2/MCP-1, and CXCL8/IL-8. Quercetin was the only ligand capable of antagonizing IS-induced AhR transcriptional activity, as well as the upregulation of the endothelial AhR target genes CYP1A1 and CYP1B1. In contrast, galangin, curcumin, and I3C exhibited no inhibitory effects. Moreover, none of the tested dietary AhR ligands suppressed the IS-induced upregulation of endothelial inflammatory genes; instead, they tended to potentiate IS-induced inflammatory responses at high concentrations. In conclusion, among the AhR ligands tested, quercetin was the only one that attenuated IS-induced activation of the AhR genomic pathway in endothelial cells. However, it may also enhance IS-mediated endothelial inflammation, an effect also observed at specific concentrations of galangin, curcumin, and I3C. These findings suggest that the potential beneficial effects of natural dietary AhR ligands should be carefully considered in the context of CKD patients exhibiting high levels of indolic uremic toxins.