Protein-bound uremic toxins: new culprits of cardiovascular events in chronic kidney disease patients

Abstract

Chronic kidney disease (CKD) has been considered a major risk factor for cardiovascular diseases. Although great advances have recently been made in the pathophysiology and treatment of cardiovascular diseases, CKD remains a major global health problem. Moreover, the occurrence rates of cardiovascular events among CKD patients increase even in cases in which patients undergo hemodialysis, and the mechanisms underlying the so-called "cardiorenal syndrome" are not clearly understood. Recently, small-molecule uremic toxins have been associated with cardiovascular mortality in CKD and/or dialysis patients. These toxins range from small uncharged solutes to large protein-bound structures. In this review, we focused on protein-bound uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which are poorly removed by current dialysis techniques. Several studies have demonstrated that protein-bound uremic toxins, especially indoxyl sulfate, induce vascular inflammation, endothelial dysfunction, and vascular calcification, which may explain the relatively poor prognosis of CKD and dialysis patients. The aim of this review is to provide novel insights into the effects of indoxyl sulfate and p-cresyl sulfate on the pathogenesis of atherosclerosis.

Figures

Figure 1

Effects of indoxyl sulfate on leukocyte-endothelial interactions in a mouse model of chronic kidney disease. (A) Representative snapshots from intravital video microscopic analysis of leukocyte adhesion in femoral arteries (vessel walls indicated by dashed lines) of 5/6 nephrectomized mice with (Nx+IS) or without (Nx) indoxyl sulfate treatment. White spots represent fluorescent leukocytes labeled using intravenously injected rhodamine 6G; (B) Quantitative analysis of leukocyte adhesion to femoral arteries. Data are expressed as mean ± SEM (N = 5).

Figure 2

Effects of indoxyl sulfate on tumor necrosis factor-α (TNF-α)-induced leukocyte-endothelial interactions and expression of cell adhesion molecules. (A) Representative phase contrast micrographs showing adhesion of THP-1 cells to 100 pg/mL TNF-α-activated HUVECs with and without indoxyl sulfate (IS+ and IS−, respectively) pretreatment (2.0 mmol/L, 20 h). Arrowheads indicate adhered THP-1 cells (magnification, 200×); (B,C) Adhesion assay (B) and western blot analysis (C) of adhesion molecules in HUVECs treated with various concentrations of IS for 20 h, and then with (+) or without (−) TNF-α (100 pg/mL) for 4 h. Data from the adhesion assay are expressed as mean ± SEM (N = 10). *P < 0.01 vs. TNF (+) IS (−); **P < 0.001 vs. TNF (+) IS (−). The data shown are representative of 3 independent experiments.

Figure 3

Effects of indoxyl sulfate on the vascular endothelium and cardiorenal syndrome. In renal failure conditions, levels of both pro-inflammatory cytokines and uremic toxins, such as indoxyl sulfate, are up-regulated. Indoxyl sulfate enhances cytokine-induced NF-κB and JNK signaling through oxidative stress-dependent pathways, resulting in increased expression of adhesion molecules. Indoxyl sulfate alone also mediates the release of reactive oxygen species (ROS) through activation of NAD(P)H oxidase and reduction in glutathione levels, leading to endothelial dysfunction, inhibition of proliferation, delayed wound healing, and release of tissue factor. These indoxyl sulfate-mediated toxic effects may lead to atherosclerosis resulting in a CVD, such as coronary artery disease.