Abstract
Endothelial dysfunction in uremia can result in cell-to-cell junction loss and increased permeability, contributing to cardiovascular diseases (CVD) development. This study evaluated the impact of the uremic milieu on endothelial morphology and cell junction’s proteins. We evaluated (i) serum levels of inflammatory biomarkers in a cohort of chronic kidney disease (CKD) patients and the expression of VE-cadherin and Zonula Occludens-1 (ZO-1) junction proteins on endothelial cells (ECs) of arteries removed from CKD patients during renal transplant; (ii) ECs morphology in vitro under different uremic conditions, and (iii) the impact of uremic toxins p-cresyl sulfate (PCS), indoxyl sulfate (IS), and inorganic phosphate (Pi) as well as of total uremic serum on VE-cadherin and ZO-1 gene and protein expression in cultured ECs. We found that the uremic arteries had lost their intact and continuous endothelial morphology, with a reduction in VE-cadherin and ZO-1 expression. In cultured ECs, both VE-cadherin and ZO-1 protein expression decreased, mainly after exposure to Pi and uremic serum groups. VE-cadherin mRNA expression was reduced while ZO-1 was increased after exposure to PCS, IS, Pi, and uremic serum. Our findings show that uremia alters cell-to-cell junctions leading to an increased endothelial damage. This gives a new perspective regarding the pathophysiological role of uremia in intercellular junctions and opens new avenues to improve cardiovascular outcomes in CKD patients.
Highlights
The constant endothelium aggression resulting from the interaction between uremic toxins and endothelial cells (ECs), with cellular phenotype alteration, may result in elevated plasma levels of vascular inflammatory biomarkers, such as IL-8 and MCP-1 (CCL2) cytokines and adhesion moleculesVCAM-1 and ICAM-1 [1]
The present study aims at investigating systematically the effect of uremia on the expression of VE-cadherin and Zonula Occludens-1 (ZO-1) in endothelial cell junctions, to better understand the pathophysiological role of uremia in disruption of intercellular junctions and cardiovascular impact, allowing us to gain new perspectives, leading to the discovery of novel therapeutic strategies, that might help in preventing the development of cardiovascular complications in chronic kidney disease (CKD) patients
Cell viability significantly decreased in cells treated with p-cresyl sulfate (PCS) maximum uremic (PCSm), Is maximum uremic (Ism), and Pi4 (P < 0.0001) when compared to control (Figure 3)
Summary
The constant endothelium aggression resulting from the interaction between uremic toxins and endothelial cells (ECs), with cellular phenotype alteration, may result in elevated plasma levels of vascular inflammatory biomarkers, such as IL-8 and MCP-1 (CCL2) cytokines and adhesion molecules. VCAM-1 and ICAM-1 [1] Serum levels of these biomarkers increase during advanced chronic kidney disease (CKD) stages, suggesting a link between vascular activation, inflammation and uremic toxicity [2,3]. The uremic toxins can induce active free radicals [4], endothelial microparticle production [5], and cytoskeletal remodeling, while resulting in increased permeability, interfering with the intercellular junctions [6,7]. Endothelial cell junctions such as tight junctions (TJs), adherent junctions (AJs), and gap junctions (GJs) control important functions in cell homeostasis [8]. The present study aims at investigating systematically the effect of uremia on the expression of VE-cadherin and ZO-1 in endothelial cell junctions, to better understand the pathophysiological role of uremia in disruption of intercellular junctions and cardiovascular impact, allowing us to gain new perspectives, leading to the discovery of novel therapeutic strategies, that might help in preventing the development of cardiovascular complications in CKD patients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
