Abstract
The goal of our study was to investigate the impact of p-cresylsulfate (PCS) on the barrier integrity in human umbilical vein endothelial cell (HUVEC) monolayers and the renal artery of chronic kidney disease (CKD) patients. We measured changes in the transendothelial electrical resistance (TEER) of HUVEC monolayers treated with PCS (0.1–0.2 mM) similar to serum levels of CKD patients. A PCS dose (0.2 mM) significantly decreased TEER over a 48-h period. Both PCS doses (0.1 and 0.2 mM) significantly decreased TEER over a 72-h period. Inter-endothelial gaps were observed in HUVECs following 48 h of PCS treatment by immunofluorescence microscopy. We also determined whether PCS induced the phosphorylation of VE-cadherin at tyrosine 658 (Y658) mediated by the phosphorylation of Src. Phosphorylated VE-cadherin (Y658) and phosphorylated Src levels were significantly higher when the cells were treated with 0.1 and 0.2 mM PCS, respectively, compared to the controls. The endothelial barrier dysfunction in the arterial intima in CKD patients was evaluated by endothelial leakage of immunoglobulin G (IgG). Increased endothelial leakage of IgG was related to the declining kidney function in CKD patients. Increased endothelial permeability induced by uremic toxins, including PCS, suggests that uremic toxins induce endothelial barrier dysfunction in CKD patients and Src-mediated phosphorylation of VE-cadherin is involved in increased endothelial permeability induced by PCS exposure.
Highlights
Chronic kidney disease (CKD) is a global health problem
To conduct studies on endothelial dysfunction induced by PCS exposure, the PCS compound was synthesized and its identity was confirmed by electrospray ionization mass spectrometry (ESI-MS)
To investigate whether PCS exposure led to alterations in endothelial permeability, we measured the changes in the transendothelial electrical resistance (TEER) of endothelial cell monolayers
Summary
Chronic kidney disease (CKD) is a global health problem. As CKD gradually progresses and the body tissues gradually accumulate uremic toxins, hemodialysis treatment is necessary for CKD patients.Toxins 2020, 12, 62; doi:10.3390/toxins12020062 www.mdpi.com/journal/toxinsprotein-bound retention solutes such as indoxylsulfate (IS) and p-cresylsulfate (PCS) are not efficiently eliminated by traditional hemodialysis [1,2]. Chronic kidney disease (CKD) is a global health problem. As CKD gradually progresses and the body tissues gradually accumulate uremic toxins, hemodialysis treatment is necessary for CKD patients. Protein-bound retention solutes such as indoxylsulfate (IS) and p-cresylsulfate (PCS) are not efficiently eliminated by traditional hemodialysis [1,2]. The serum levels of both IS and PCS are elevated in CKD and end stage kidney disease (ESKD) dialysis patients [4,5,6]. High serum levels of protein-bound retention solutes such as PCS and IS are associated with increased risk and mortality of cardiovascular disease (CVD) such as atherosclerosis in CKD or hemodialysis patients [7,8,9,10,11,12]
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