Endothelial aging may be induced early in pathological situations. The uremic toxins indoxyl sulfate (IS) and p-cresol (PC) accumulate in the plasma of chronic kidney disease (CKD) patients, causing accelerated endothelial aging, increased cardiovascular events and mortality. However, the mechanisms by which uremic toxins exert their deleterious effects on endothelial aging are not yet fully known. Thus, the aim of the present study is to determine the effects of IS and PC on endothelial damage and early senescence in cultured human umbilical vein endothelial cells (HUVECs). Hence, we establish an in vitro model of endothelial damage mediated by different passages of HUVECs and stimulated with different concentrations of IS and PC to evaluate functional effects on the vascular endothelium. We observe that cell passage-induced senescence is associated with apoptosis, ROS production and decreased endothelial proliferative capacity. Similarly, we observe that IS and PC cause premature aging in a dose-dependent manner, altering HUVECs’ regenerative capacity, and decreasing their cell migration and potential to form vascular structures in vitro. In conclusion, IS and PC cause accelerated aging in HUVECs, thus contributing to endothelial dysfunction associated with CKD progression.

A selenium-containing metal-organic framework with remarkable antioxidant capacity and ROS-scavenging activity was constructed by a controlled de novo encapsulation approach of a glycoconjugate mimetic, specifically a sp²-iminoglycolipid bearing a selenoureido fragment (DSeU), within a zeolitic-imidazolate framework exoskeleton. Biocompatible and homogeneous nanosized particles of ~70 nm (DSeU@ZIF8) were obtained, which could be efficiently internalized in cells, overcoming the poor solubility in biological media and limited bioavailability of glycolipids. The ZIF-particle served as nanocarrier for the intracellular delivery of the selenocompound to cells, promoted by the acidic pH inside endosomes/lysosomes. As demonstrated by in vitro studies, the designed DSeU@ZIF8 nanoparticles displayed a high antioxidant activity at low doses; lower intracellular ROS levels were observed upon the uptake of DSeU@ZIF8 by human endothelial cells. Even more interesting was the finding that these DSeU@ZIF8 particles were able to reverse to a certain level the oxidative stress induced in cells by pre-treatment with an oxidizing agent. This possibility of modulating the oxidative stress in living cells may have important implications in the treatment of diverse pathological complications that are generally accompanied with elevated ROS levels.

Atherosclerosis is initiated by the activation of endothelial cells that allows monocyte adhesion and transmigration through the vascular wall. The accumulation of uremic toxins such as indoxyl sulphate (IS) and p-cresol (PC) has been associated with atherosclerosis. Currently, miRNAs play a crucial role in the regulation of monocyte activation, adhesion, and trans-endothelial migration. The aim of the present study is to evaluate the effect of IS and PC on monocyte adhesion and migration processes in monocytes co-cultured with endothelial cells as well as to determine the underlying mechanisms. The incubation of HUVECs and THP-1 cells with both IS and PC toxins resulted in an increased migratory capacity of THP-1 cells. Furthermore, the exposure of THP-1 cells to both uremic toxins resulted in the upregulation of BMP-2 and miRNAs-126-3p, -146b-5p, and -223-3p, as well as the activation of nuclear factor kappa B (NF-κB) and a decrease in its inhibitor IĸB. Uremic toxins, such as IS and PC, enhance the migratory and adhesion capacity of THP-1 cells to the vascular endothelium. These toxins, particularly PC, contribute significantly to uremia-associated vascular disease by increasing in THP-1 cells the expression of BMP-2, NF-κB, and key miRNAs associated with the development of atherosclerotic vascular diseases.

Background/Objectives: It would be desirable to reduce the intake of inorganic phosphate (P), which is easily absorbed and is associated with cardiovascular disease. The phosphate-to-urea nitrogen ratio (P/UUN) in urine should reflect the proportion of inorganic P ingested relative to protein intake. In this manuscript, we will refer to this parameter as P/UUN, which is conceptually equivalent to the phosphate-to-urea ratio (P/U). These studies aim to evaluate whether an increased intake of inorganic P translates into an increase in the P/UUN. Methods: A total of 18 healthy volunteers (Study-1) and 18 chronic kidney disease patients (Study-2) were included. At baseline, all participants completed a 3-day dietary survey, and on the third day collected a 24 h urine sample. In Study-2, blood samples were also obtained. Participants were then stratified into three groups (6 per group) for a 3-day dietary intervention: control group: maintained their usual diet; soda group: consumed soda zero, a source of added inorganic P; and processed cheese group: consumed fresh processed cheese, which includes both organic and inorganic P additives. At last visit, all participants again completed a 3-day dietary survey and collected a 24 h urine sample (and blood samples in Study-2). Dietary P intake was estimated using two tools: the diet calibrator and the Spanish Food Composition Database (BEDCA). Results: After the intervention, neither BEDCA nor the diet calibrator was able to provide an accurate measurement of inorganic P ingested. However, only in the soda group, P/UUN increased in both studies (p = 0.046 and 0.047). In Study-2, the levels of FGF23 and klotho remained unchanged (p = 0.9 and p = 0.7, respectively). Conclusions: These findings suggest that urinary P/UUN ratio may be a useful biomarker to monitor changes in inorganic P intake and could help to individualize dietary recommendations to reduce inorganic P exposure without restricting protein intake.