How do Uremic Toxins Affect the Endothelium?

Abstract

Uremic toxins can induce endothelial dysfunction in patients with chronic kidney disease (CKD). Indeed, the structure of the endothelial monolayer is damaged in CKD, and studies have shown that the uremic toxins contribute to the loss of cell–cell junctions, increasing permeability. Membrane proteins, such as transporters and receptors, can mediate the interaction between uremic toxins and endothelial cells. In these cells, uremic toxins induce oxidative stress and activation of signaling pathways, including the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways leads to overexpression of proinflammatory (e.g., monocyte chemoattractant protein-1, E-selectin) and prothrombotic (e.g., tissue factor) proteins. Uremic toxins also induce the formation of endothelial microparticles (EMPs), which can lead to the activation and dysfunction of other cells, and modulate the expression of microRNAs that have an important role in the regulation of cellular processes. The resulting endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases, such as atherosclerosis and thrombotic events. Therefore, uremic toxins as well as the pathways they modulated may be potential targets for therapies in order to improve treatment for patients with CKD.

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

“…Both IS and PCS in high concentrations lead to an increase in MCP-1 (monocyte chemoattractant protein-1) expression, attracting macrophages and monocytes to the injured endothelium during the inflammatory process (Cohen, 2020). The uremic toxins are responsible for modulation of adhesion molecules such as P-selectin, E-selectin, ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1), promoting the infiltration of macrophages and monocytes in endothelium (Da Cunha et al, 2020). In CKD patients, PCS can activate macrophages and also interferes in antigen processing impairing the adaptative immune response (Cohen, 2020).…”

Uremic Toxins, Oxidative Stress, Atherosclerosis in Chronic Kidney Disease, and Kidney Transplantation

“…It is characterized by increased oxidative stress, expression of proinflammatory and prothrombotic molecules, and decreased capabilities of endothelial repair. Uremic toxins can contribute to these deleterious effects on the endothelium [ 36 – 38 ]. There is a correlation between inflammation, oxidative stress, endothelial dysfunction, and markers of vasculopathy and kidney function [ 39 – 41 ].…”

“…Uremic toxins induce inflammation in endothelial cells (ECs) and stimulate the cross-talk between ECs and macrophages [ 14 , 35 – 37 ]. In the response to the injury, the concentration of cytokines is increased leading to the activation of endothelial, resident vascular cells, and circulating monocytes [ 8 , 11 , 36 – 38 ]. Uremic toxins (pbUTs, phosphates, and FGF23) increase the expression of adhesion molecules (E-selectin, P-selectin, ICAM-1, and VCAM-1) promoting the infiltration of monocytes and macrophages in the activated endothelium [ 11 , 13 , 15 , 16 , 20 , 35 , 37 ].…”

Thrombolome and Its Emerging Role in Chronic Kidney Diseases

“…The accumulation of uremic toxins in renal failure is highly thrombogenic and exerts toxic effects on the vessel wall [ 45 ]. This is possibly due to the induction of platelet dysfunction and modulation of their responsiveness as well as harmful effects on vascular endothelium and a decreased production of nitric oxide [ 46 ]. It was determined that TMAO can directly modulate platelet hyperresponsiveness and increase the clot formation rate.…”