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Toxins
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The Endothelial Effects of Uremic Toxins
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The Endothelial Effects of Uremic Toxins

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Uremic Toxins".

Deadline for manuscript submissions: closed (31 August 2019) | Viewed by 39312

Special Issue Editors

Prof. Stéphane Burtey

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Guest Editor
Aix Marseille Univ, INSERM, INRAE, C2VN, Marseille, France.
Interests: uremic toxins; aryl hydrocarbon receptor; endothelium
Prof. Dr. Suguru Yamamoto

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Guest Editor
Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
Interests: clinical study about uremic toxins-related disease; basic study about uremic toxins-related functional abnormalities of macrophages
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

The number of patients who have chronic kidney disease (CKD) has increased around the world. There are many therapeutic options and clinical guidelines for kidney disease; however, clinical outcomes of CKD patients, especially those undergoing dialysis treatment, are still poor owing to various CKD-related systemic diseases. For example, the incidence of cardiovascular events increases with the progression of CKD, and lipid lowering therapy has not shown a significant effect on dialysis patients. Thus, it is thought that there are several CKD-specific risk factors for CKD-related systemic disease in addition to traditional factors.

Uremic toxins are solutes retained in CKD patients and associated with various uremic syndromes. Recent clinical and basic studies suggest that various kinds of uremic toxins are associated with CKD-related systemic disease. Of course, uremic toxins induce acceleration of atherosclerosis and vascular calcification as well as clinical cardiovascular events. The functional abnormalities of endothelial cells are critical for pathogenesis not only in cardiovascular disease but also in other general systemic diseases, and uremic toxins are associated with them.

This Special Issue entitled ‘The Endothelial Effects of Uremic Toxins’ focuses on understanding the roles of uremic toxins in endothelial dysfunctions which lead to various CKD-related systemic diseases. Papers that assess any kinds of uremic toxins and endothelial functions in basic studies and evaluate the role of toxins with several biomarkers or clinical outcomes that are related with endothelial effects in clinical studies are welcome.

Prof. Dr. Stéphane Burtey
Prof. Dr. Suguru Yamamoto
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • uremic toxins
  • endothelial cells
  • atherosclerosis
  • vascular calcification
  • indoxyl sulfate
  • p-cresyl sulfate
  • chronic kidney disease
  • dialysis

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Published Papers (7 papers)

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Research

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15 pages, 3126 KiB  
Article
P-Cresylsulfate, the Protein-Bound Uremic Toxin, Increased Endothelial Permeability Partly Mediated by Src-Induced Phosphorylation of VE-Cadherin
by Shih-Chieh Chen, Shin-Yin Huang, Chia-Chun Wu and Chiung-Fang Hsu
Toxins 2020, 12(2), 62; https://doi.org/10.3390/toxins12020062 - 21 Jan 2020
Cited by 9 | Viewed by 2964
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Endothelial Effects of Uremic Toxins)
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11 pages, 537 KiB  
Article
Association between Serum Indoxyl Sulfate Levels and Endothelial Function in Non-Dialysis Chronic Kidney Disease
by Chih-Hsien Wang, Yu-Hsien Lai, Chiu-Huang Kuo, Yu-Li Lin, Jen-Pi Tsai and Bang-Gee Hsu
Toxins 2019, 11(10), 589; https://doi.org/10.3390/toxins11100589 - 11 Oct 2019
Cited by 25 | Viewed by 3323
Abstract
Indoxyl sulfate (IS), a product metabolized from tryptophan, is negatively correlated with renal function and cardiovascular diseases in patients with chronic kidney disease (CKD). We investigated the association between serum IS levels and endothelial function in patients with CKD. Fasting blood samples were [...] Read more.
Indoxyl sulfate (IS), a product metabolized from tryptophan, is negatively correlated with renal function and cardiovascular diseases in patients with chronic kidney disease (CKD). We investigated the association between serum IS levels and endothelial function in patients with CKD. Fasting blood samples were obtained from 110 patients with stages 3–5 CKD. The endothelial function, represented by vascular reactivity index (VRI), was measured non-invasively using digital thermal monitoring. Serum IS levels were determined using liquid chromatography–mass spectrometry. Twenty-one (19.1%), 36 (32.7%), and 53 (48.2%) patients had poor (VRI < 1.0), intermediate (1.0 ≤ VRI < 2.0), and good (VRI ≥ 2.0) vascular reactivity. By univariate linear regression analysis, a higher prevalence of smoking, advanced age, higher systolic, and diastolic blood pressure (DBP), elevated levels of serum phosphorus, blood urea nitrogen, creatinine, and IS were negatively correlated with VRI values, but estimated glomerular filtration rate negatively associated with VRI values. After being adjusted by using multivariate stepwise linear regression analysis, DBP and IS levels were significantly negatively associated with VRI values in CKD patients. We concluded that IS level associated inversely with VRI values and had a modulating role in endothelial function in patients with stages 3–5 CKD. Full article
(This article belongs to the Special Issue The Endothelial Effects of Uremic Toxins)
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18 pages, 3609 KiB  
Article
Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1
by Jiayi Pei, Rio Juni, Magdalena Harakalova, Dirk J. Duncker, Folkert W. Asselbergs, Pieter Koolwijk, Victor van Hinsbergh, Marianne C. Verhaar, Michal Mokry and Caroline Cheng
Toxins 2019, 11(8), 454; https://doi.org/10.3390/toxins11080454 - 2 Aug 2019
Cited by 14 | Viewed by 4168
Abstract
Indoxyl sulfate (IS) is an accumulative protein-bound uremic toxin found in patients with kidney disease. It is reported that IS impairs the vascular endothelium, but a comprehensive overview of all mechanisms active in IS-injury currently remains lacking. Here we performed RNA sequencing in [...] Read more.
Indoxyl sulfate (IS) is an accumulative protein-bound uremic toxin found in patients with kidney disease. It is reported that IS impairs the vascular endothelium, but a comprehensive overview of all mechanisms active in IS-injury currently remains lacking. Here we performed RNA sequencing in human umbilical vein endothelial cells (HUVECs) after IS or control medium treatment and identified 1293 genes that were affected in a IS-induced response. Gene enrichment analysis highlighted pathways involved in altered vascular formation and cell metabolism. We confirmed these transcriptome profiles at the functional level by demonstrating decreased viability and increased cell senescence in response to IS treatment. In line with the additional pathways highlighted by the transcriptome analysis, we further could demonstrate that IS exposure of HUVECs promoted tubule formation as shown by the increase in total tubule length in a 3D HUVECs/pericytes co-culture assay. Notably, the pro-angiogenic response of IS and increased ROS production were abolished when CYP1B1, one of the main target genes that was highly upregulated by IS, was silenced. This observation indicates IS-induced ROS in endothelial cells is CYP1B1-dependent. Taken together, our findings demonstrate that IS promotes angiogenesis and CYP1B1 is an important factor in IS-activated angiogenic response. Full article
(This article belongs to the Special Issue The Endothelial Effects of Uremic Toxins)
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Review

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34 pages, 1686 KiB  
Review
Hemolysis Derived Products Toxicity and Endothelium: Model of the Second Hit
by Marie Frimat, Idris Boudhabhay and Lubka T. Roumenina
Toxins 2019, 11(11), 660; https://doi.org/10.3390/toxins11110660 - 13 Nov 2019
Cited by 57 | Viewed by 11986
Abstract
Vascular diseases are multifactorial, often requiring multiple challenges, or ‘hits’, for their initiation. Intra-vascular hemolysis illustrates well the multiple-hit theory where a first event lyses red blood cells, releasing hemolysis-derived products, in particular cell-free heme which is highly toxic for the endothelium. Physiologically, [...] Read more.
Vascular diseases are multifactorial, often requiring multiple challenges, or ‘hits’, for their initiation. Intra-vascular hemolysis illustrates well the multiple-hit theory where a first event lyses red blood cells, releasing hemolysis-derived products, in particular cell-free heme which is highly toxic for the endothelium. Physiologically, hemolysis derived-products are rapidly neutralized by numerous defense systems, including haptoglobin and hemopexin which scavenge hemoglobin and heme, respectively. Likewise, cellular defense mechanisms are involved, including heme-oxygenase 1 upregulation which metabolizes heme. However, in cases of intra-vascular hemolysis, those systems are overwhelmed. Heme exerts toxic effects by acting as a damage-associated molecular pattern and promoting, together with hemoglobin, nitric oxide scavenging and ROS production. In addition, it activates the complement and the coagulation systems. Together, these processes lead to endothelial cell injury which triggers pro-thrombotic and pro-inflammatory phenotypes. Moreover, among endothelial cells, glomerular ones display a particular susceptibility explained by a weaker capacity to counteract hemolysis injury. In this review, we illustrate the ‘multiple-hit’ theory through the example of intra-vascular hemolysis, with a particular focus on cell-free heme, and we advance hypotheses explaining the glomerular susceptibility observed in hemolytic diseases. Finally, we describe therapeutic options for reducing endothelial injury in hemolytic diseases. Full article
(This article belongs to the Special Issue The Endothelial Effects of Uremic Toxins)
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12 pages, 682 KiB  
Review
Uremic Toxins and Atrial Fibrillation: Mechanisms and Therapeutic Implications
by Fumi Yamagami, Kazuko Tajiri, Dai Yumino and Masaki Ieda
Toxins 2019, 11(10), 597; https://doi.org/10.3390/toxins11100597 - 13 Oct 2019
Cited by 12 | Viewed by 5057
Abstract
Atrial fibrillation (AF) is the most prevalent arrhythmia in the general population. There is a close association between chronic kidney disease (CKD) and AF. In recent years, attention has been focused on the relationship between AF and uremic toxins, including indoxyl sulfate (IS). [...] Read more.
Atrial fibrillation (AF) is the most prevalent arrhythmia in the general population. There is a close association between chronic kidney disease (CKD) and AF. In recent years, attention has been focused on the relationship between AF and uremic toxins, including indoxyl sulfate (IS). Several animal studies have shown that IS promotes the development and progression of AF. IS has been shown to cause fibrosis and inflammation in the myocardium and exacerbate AF by causing oxidative stress and reducing antioxidative defense. Administration of AST-120, an absorbent of uremic toxins, decreases uremic toxin-induced AF in rodents. We have recently reported that patients with a higher serum IS level exhibit a higher rate of AF recurrence after catheter ablation, with serum IS being a significant predictor of AF recurrence. In this review, we discuss the possible mechanisms behind the AF-promoting effects of uremic toxins and summarize the reported clinical studies of uremic toxin-induced AF. Full article
(This article belongs to the Special Issue The Endothelial Effects of Uremic Toxins)
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16 pages, 1009 KiB  
Review
Endothelial Toxicity of High Glucose and its by-Products in Diabetic Kidney Disease
by Laetitia Dou and Noémie Jourde-Chiche
Toxins 2019, 11(10), 578; https://doi.org/10.3390/toxins11100578 - 5 Oct 2019
Cited by 39 | Viewed by 5749
Abstract
Alterations of renal endothelial cells play a crucial role in the initiation and progression of diabetic kidney disease. High glucose per se, as well as glucose by-products, induce endothelial dysfunction in both large vessels and the microvasculature. Toxic glucose by-products include advanced glycation [...] Read more.
Alterations of renal endothelial cells play a crucial role in the initiation and progression of diabetic kidney disease. High glucose per se, as well as glucose by-products, induce endothelial dysfunction in both large vessels and the microvasculature. Toxic glucose by-products include advanced glycation end products (AGEs), a group of modified proteins and/or lipids that become glycated after exposure to sugars, and glucose metabolites produced via the polyol pathway. These glucose-related endothelio-toxins notably induce an alteration of the glomerular filtration barrier by increasing the permeability of glomerular endothelial cells, altering endothelial glycocalyx, and finally, inducing endothelial cell apoptosis. The glomerular endothelial dysfunction results in albuminuria. In addition, high glucose and by-products impair the endothelial repair capacities by reducing the number and function of endothelial progenitor cells. In this review, we summarize the mechanisms of renal endothelial toxicity of high glucose/glucose by-products, which encompass changes in synthesis of growth factors like TGF-β and VEGF, induction of oxidative stress and inflammation, and reduction of NO bioavailability. We finally present potential therapies to reduce endothelial dysfunction in diabetic kidney disease. Full article
(This article belongs to the Special Issue The Endothelial Effects of Uremic Toxins)
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16 pages, 5225 KiB  
Review
Endothelial Microparticles in Uremia: Biomarkers and Potential Therapeutic Targets
by Giane Favretto, Regiane Stafim da Cunha, Maria Aparecida Dalboni, Rodrigo Bueno de Oliveira, Fellype de Carvalho Barreto, Ziad A. Massy and Andréa Emilia Marques Stinghen
Toxins 2019, 11(5), 267; https://doi.org/10.3390/toxins11050267 - 13 May 2019
Cited by 21 | Viewed by 5214
Abstract
Endothelial microparticles (EMPs) are vesicles derived from cell membranes, which contain outsourced phosphatidylserine and express adhesion molecules, such as cadherin, intercellular cell adhesion molecule-1 (ICAM-1), E-selectin, and integrins. EMPs are expressed under physiological conditions and continue circulating in the plasma. However, in pathologic [...] Read more.
Endothelial microparticles (EMPs) are vesicles derived from cell membranes, which contain outsourced phosphatidylserine and express adhesion molecules, such as cadherin, intercellular cell adhesion molecule-1 (ICAM-1), E-selectin, and integrins. EMPs are expressed under physiological conditions and continue circulating in the plasma. However, in pathologic conditions their levels increase, and they assume a pro-inflammatory and pro-coagulant role via interactions with monocytes; these effects are related to the development of atherosclerosis. Chronic kidney dysfunction (CKD) characterizes this dysfunctional scenario through the accumulation of uremic solutes in the circulating plasma, whose toxicity is related to the development of cardiovascular diseases. Therefore, this review aims to discuss the formation of EMPs and their biological effects in the uremic environment. Data from previous research demonstrate that uremic toxins are closely associated with the activation of inflammatory biomarkers, cardiovascular dysfunction processes, and the release of EMPs. The impact of a decrease in circulating EMPs in clinical studies has not yet been evaluated. Thus, whether MPs are biochemical markers and/or therapeutic targets has yet to be established. Full article
(This article belongs to the Special Issue The Endothelial Effects of Uremic Toxins)
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