Abstract
The protein-bound uremic toxins, indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are considered to be harmful vascular toxins. Arterial media calcification, or the deposition of calcium phosphate crystals in the arteries, contributes significantly to cardiovascular complications, including left ventricular hypertrophy, hypertension, and impaired coronary perfusion in the elderly and patients with chronic kidney disease (CKD) and diabetes. Recently, we reported that both IS and PCS trigger moderate to severe calcification in the aorta and peripheral vessels of CKD rats. This review describes the molecular and cellular mechanisms by which these uremic toxins induce arterial media calcification. A complex interplay between inflammation, coagulation, and lipid metabolism pathways, influenced by epigenetic factors, is crucial in IS/PCS-induced arterial media calcification. High levels of glucose are linked to these events, suggesting that a good balance between glucose and lipid levels might be important. On the cellular level, effects on endothelial cells, which act as the primary sensors of circulating pathological triggers, might be as important as those on vascular smooth muscle cells. Endothelial dysfunction, provoked by IS and PCS triggered oxidative stress, may be considered a key event in the onset and development of arterial media calcification. In this review a number of important outstanding questions such as the role of miRNA’s, phenotypic switching of both endothelial and vascular smooth muscle cells and new types of programmed cell death in arterial media calcification related to protein-bound uremic toxins are put forward and discussed.
Highlights
During chronic kidney disease (CKD), uremic retention solutes accumulate in the bloodstream due to progressive kidney function loss.Three classes of uremic retention solutes exist:(i) low-molecular-weight water-soluble solutes (500 Da), and (iii) protein-bound solutes
This latter class is characterized by a limited dialytic removal due to the high molecular weight of the protein complexes that complicates their movement across the dialysis membrane [1]
Our laboratory recently reported that both indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are important harmful vascular toxins, as they trigger moderate to severe arterial media calcification in CKD rats, which goes along with the activation of inflammation and coagulation pathways linked with increased circulating glucose levels and insulin resistance
Summary
During chronic kidney disease (CKD), uremic retention solutes accumulate in the bloodstream due to progressive kidney function loss. An explanation might be (i) alterations in colon microbiome attributed in part to dietary restrictions in CKD patients [9], (ii) modulation of IS and PCS transporters [10] and (iii) residual kidney function [11] This inter-patient variability might influence the interpretation on the association between of IS and PCS concentrations and clinical outcomes. Shafi et al reported no association between total IS and PCS serum concentrations with cardiac death, sudden cardiac death, and first cardiovascular event [14] These conflicting clinical associations demand for experimental study designs to unravel the role of IS and PCS in cardiovascular disease, which is crucial, as cardiovascular defects account for 50% of all deaths in CKD patients [15], having high serum IS and PCS levels.
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