Special Issue "Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease"

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

Deadline for manuscript submissions: 30 September 2021.

Special Issue Editor

Dr. Andrew R. Kompa
E-Mail Website
Guest Editor
Affiliation: University of Melbourne, St Vincent’s Hospital, Fitzroy, Victoria, Australia
Interests: ventricular remodelling and fibrosis; animal models of cardiorenal disease; uremic toxins; chronic kidney disease; cardiovascular disease; pathways involved in disease progression; inflammation in cardiac and renal disease

Special Issue Information

Dear Colleagues,

CKD is clearly linked to increased adverse cardiovascular outcomes, with 50% mortality in patients with end-stage kidney disease (ESKD) a result of accelerated cardiovascular disease (CVD). Death from cardiovascular causes is 10–30 times more common in patients with CKD than in matched segments of the general population. Patients with CKD exhibit unique characteristics, which include endothelial dysfunction, atherogenesis, vascular remodelling, calcification and inflammation, and extensive interstitial fibrosis, as well as myocardial hypertrophy, collectively termed ‘uraemic cardiomyopathy’.
Serum levels of small molecule protein bound uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, are elevated in the serum of CKD patients and have been reported to contribute to the pathogenesis and progression of cardiovascular and renal disease. Studies have demonstrated the deleterious effects of uremic toxins in cardiac, renal, vascular, and immune cells, and in tissues from human and animal models of CKD. These adverse effects are mediated by numerous signalling pathways which result in inflammation, oxidative stress, senescence and apoptosis. Identifying the mechanisms by which uremic toxins activate these processes, therapeutic strategies can be developed to mitigate their harmful actions and alleviate disease progression.
The focus of this Special Issue will include original research articles and reviews on mechanisms by which uremic toxins exert their adverse effects in cell lines, ex vivo tissue studies and animal models of CKD and/or models of cardiovascular disease, with the aim of identifying potentially novel therapeutic targets.

Dr. Andrew R. Kompa
Guest Editor

Manuscript Submission Information

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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 2400 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
  • signalling pathways
  • cardiovascular disease
  • chronic kidney disease
  • vascular remodelling
  • cardiac remodelling
  • fibrosis
  • inflammation
  • cell signalling

Published Papers (4 papers)

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Research

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Article
Uremic Apelin and Leucocytic Angiotensin-Converting Enzyme 2 in CKD Patients
Toxins 2020, 12(12), 742; https://doi.org/10.3390/toxins12120742 - 26 Nov 2020
Viewed by 526
Abstract
Apelin peptides (APLN) serve as second substrates for angiotensin-converting enzyme 2 (ACE2) and, in contrast to angiotensin II (AngII), exert blood-pressure lowering and vasodilatation effects through binding to G-coupled APLN receptor (APLNR). ACE2-mediated cleavage of the APLN may reduce its vasodilatory effects, but [...] Read more.
Apelin peptides (APLN) serve as second substrates for angiotensin-converting enzyme 2 (ACE2) and, in contrast to angiotensin II (AngII), exert blood-pressure lowering and vasodilatation effects through binding to G-coupled APLN receptor (APLNR). ACE2-mediated cleavage of the APLN may reduce its vasodilatory effects, but decreased ACE2 may potentiate the hypotensive properties of APLN. The role of APLN in uremia is unclear. We investigated the correlations between serum-APLN, leucocytic APLNR, and ACE2 in 32 healthy controls (NP), 66 HD, and 24 CKD3–5 patients, and the impact of APLN peptides on monocytic behavior and ACE2 expression under uremic conditions in vitro. We observed that serum APLN and leucocytic APLNR or SLCO2B1 were significantly elevated in uremic patients and correlated with decreased ACE2 on uremic leucocytes. APLN-treated THP-1 monocytes revealed significantly increased APLNR and ACE2, and reduced TNFa, IL-6, and MCSF. Uremic toxins induced a dramatic increase of miR-421 followed by significant reduction of ACE2 transcripts, partially counteracted with APLN-13 and -36. APLN-36 triggered the most potent transmigration and reduction of endothelial adhesion. These results suggest that although APLN peptides may partly protect against the decay of monocytic ACE2 transcripts, uremic milieu is the most dominant modulator of local ACE2, and likely to contribute to the progression of atherosclerosis. Full article
(This article belongs to the Special Issue Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease)
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Review

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Review
Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets
Toxins 2021, 13(2), 142; https://doi.org/10.3390/toxins13020142 - 13 Feb 2021
Cited by 2 | Viewed by 1098
Abstract
Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound [...] Read more.
Chronic kidney disease (CKD) is a progressive loss of renal function. The gradual decline in kidney function leads to an accumulation of toxins normally cleared by the kidneys, resulting in uremia. Uremic toxins are classified into three categories: free water-soluble low-molecular-weight solutes, protein-bound solutes, and middle molecules. CKD patients have increased risk of developing cardiovascular disease (CVD), due to an assortment of CKD-specific risk factors. The accumulation of uremic toxins in the circulation and in tissues is associated with the progression of CKD and its co-morbidities, including CVD. Although numerous uremic toxins have been identified to date and many of them are believed to play a role in the progression of CKD and CVD, very few toxins have been extensively studied. The pathophysiological mechanisms of uremic toxins must be investigated further for a better understanding of their roles in disease progression and to develop therapeutic interventions against uremic toxicity. This review discusses the renal and cardiovascular toxicity of uremic toxins indoxyl sulfate, p-cresyl sulfate, hippuric acid, TMAO, ADMA, TNF-α, and IL-6. A focus is also placed on potential therapeutic targets against uremic toxicity. Full article
(This article belongs to the Special Issue Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease)
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Review
Indoxyl Sulfate, a Tubular Toxin, Contributes to the Development of Chronic Kidney Disease
Toxins 2020, 12(11), 684; https://doi.org/10.3390/toxins12110684 - 29 Oct 2020
Cited by 4 | Viewed by 843
Abstract
Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial [...] Read more.
Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-β1 (TGF-β1), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-β1, monocyte chemotactic protein-1 and α-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline. Full article
(This article belongs to the Special Issue Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease)
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Review
Indoxyl Sulfate, a Uremic Endotheliotoxin
Toxins 2020, 12(4), 229; https://doi.org/10.3390/toxins12040229 - 05 Apr 2020
Cited by 20 | Viewed by 2039
Abstract
Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)—derived from tryptophan metabolism—accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial [...] Read more.
Chronic kidney disease (CKD) is associated with a high prevalence of cardiovascular diseases. During CKD, the uremic toxin indoxyl sulfate (IS)—derived from tryptophan metabolism—accumulates. IS is involved in the pathophysiology of cardiovascular complications. IS can be described as an endotheliotoxin: IS induces endothelial dysfunction implicated in cardiovascular morbidity and mortality during CKD. In this review, we describe clinical and experimental evidence for IS endothelial toxicity and focus on the various molecular pathways implicated. In patients with CKD, plasma concentrations of IS correlate with cardiovascular events and mortality, with vascular calcification and atherosclerotic markers. Moreover, IS induces a prothrombotic state and impaired neovascularization. IS reduction by AST-120 reverse these abnormalities. In vitro, IS induces endothelial aryl hydrocarbon receptor (AhR) activation and proinflammatory transcription factors as NF-κB or AP-1. IS has a prooxidant effect with reduction of nitric oxide (NO) bioavailability. Finally, IS alters endothelial cell and endothelial progenitor cell migration, regeneration and control vascular smooth muscle cells proliferation. Reducing IS endothelial toxicity appears to be necessary to improve cardiovascular health in CKD patients. Full article
(This article belongs to the Special Issue Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease)
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