Research

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14 pages, 4375 KiB

Open AccessArticle

Aryl Hydrocarbon Receptor Inhibition Restores Indoxyl Sulfate-Mediated Endothelial Dysfunction in Rat Aortic Rings

by Cindy Nguyen, Amanda J. Edgley, Darren J. Kelly and Andrew R. Kompa

Toxins 2022, 14(2), 100; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14020100 - 26 Jan 2022

Cited by 14 | Viewed by 2766

The uremic toxin indoxyl sulfate (IS), elevated in chronic kidney disease (CKD), is known to contribute towards progressive cardiovascular disease. IS activates the aryl hydrocarbon receptor (AhR) mediating oxidative stress and endothelial dysfunction via activation of the CYP1A1 pathway. The present study examines [...] Read more.

The uremic toxin indoxyl sulfate (IS), elevated in chronic kidney disease (CKD), is known to contribute towards progressive cardiovascular disease. IS activates the aryl hydrocarbon receptor (AhR) mediating oxidative stress and endothelial dysfunction via activation of the CYP1A1 pathway. The present study examines AhR inhibition with the antagonist, CH223191, on IS-mediated impairment of vascular endothelial function and disruption of redox balance. The acute effects of IS on endothelium-dependent relaxation were assessed in aortic rings from Sprague Dawley rats exposed to the following conditions: (1) control; (2) IS (300 μM); (3) IS + CH223191 (1 μM); (4) IS + CH223191 (10 μM). Thereafter, tissues were assessed for changes in expression of redox markers. IS reduced the maximum level of endothelium-dependent relaxation (Rmax) by 42% (p < 0.001) compared to control, this was restored in the presence of increasing concentrations of CH223191 (p < 0.05). Rings exposed to IS increased expression of CYP1A1, nitro-tyrosine, NADPH oxidase 4 (NOX4), superoxide, and reduced eNOS expression (p < 0.05). CH223191 (10 μM) restored expression of these markers back to control levels (p < 0.05). These findings demonstrate the adverse impact of IS-mediated AhR activation on the vascular endothelium, where oxidative stress may play a critical role in inducing endothelial dysfunction in the vasculature of the heart and kidneys. AhR inhibition could provide an exciting novel therapy for CVD in the CKD setting. Full article

(This article belongs to the Special Issue Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease)

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19 pages, 3249 KiB

Open AccessArticle

Indoxyl Sulfate Elevated Lnc-SLC15A1-1 Upregulating CXCL10/CXCL8 Expression in High-Glucose Endothelial Cells by Sponging MicroRNAs

by Yu-Chin Huang, Tzu-Chun Tsai, Chia-Hsin Chang, Kuo-Ting Chang, Pin-Hao Ko and Liang-Chuan Lai

Toxins 2021, 13(12), 873; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13120873 - 07 Dec 2021

Cited by 4 | Viewed by 2797

Abstract

Cardiovascular disease (CVD) is the leading cause of mortality in diabetes mellitus (DM). Immunomodulatory dysfunction is a primary feature of DM, and the emergence of chronic kidney disease (CKD) in DM abruptly increases CVD mortality compared with DM alone. Endothelial injury and the [...] Read more.

Cardiovascular disease (CVD) is the leading cause of mortality in diabetes mellitus (DM). Immunomodulatory dysfunction is a primary feature of DM, and the emergence of chronic kidney disease (CKD) in DM abruptly increases CVD mortality compared with DM alone. Endothelial injury and the accumulation of uremic toxins in the blood of DM/CKD patients are known mechanisms for the pathogenesis of CVD. However, the molecular factors that cause this disproportional increase in CVD in the DM/CKD population are still unknown. Since long non-protein-coding RNAs (lncRNAs) play an important role in regulating multiple cellular functions, we used human endothelial cells treated with high glucose to mimic DM and with the uremic toxin indoxyl sulfate (IS) to mimic the endothelial injury associated with CKD. Differentially expressed lncRNAs in these conditions were analyzed by RNA sequencing. We discovered that lnc-SLC15A1-1 expression was significantly increased upon IS treatment in comparison with high glucose alone, and then cascaded the signal of chemokines CXCL10 and CXCL8 via sponging miR-27b, miR-297, and miR-150b. This novel pathway might be responsible for the endothelial inflammation implicated in augmenting CVD in DM/CKD and could be a therapeutic target with future clinical applications. Full article

(This article belongs to the Special Issue Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease)

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14 pages, 1699 KiB

Open AccessArticle

Uremic Apelin and Leucocytic Angiotensin-Converting Enzyme 2 in CKD Patients

by Bogusz Trojanowicz, Christof Ulrich and Matthias Girndt

Toxins 2020, 12(12), 742; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120742 - 26 Nov 2020

Cited by 1 | Viewed by 1757

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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11 pages, 1001 KiB

Open AccessReview

Uremic Toxins and Protein-Bound Therapeutics in AKI and CKD: Up-to-Date Evidence

by Jia-Huang Chen and Chih-Kang Chiang

Toxins 2022, 14(1), 8; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14010008 - 23 Dec 2021

Cited by 9 | Viewed by 5599

Abstract

Uremic toxins are defined as harmful metabolites that accumulate in the human body of patients whose renal function declines, especially chronic kidney disease (CKD) patients. Growing evidence demonstrates the deteriorating effect of uremic toxins on CKD progression and CKD-related complications, and removing uremic [...] Read more.

Uremic toxins are defined as harmful metabolites that accumulate in the human body of patients whose renal function declines, especially chronic kidney disease (CKD) patients. Growing evidence demonstrates the deteriorating effect of uremic toxins on CKD progression and CKD-related complications, and removing uremic toxins in CKD has become the conventional treatment in the clinic. However, studies rarely pay attention to uremic toxin clearance in the early stage of acute kidney injury (AKI) to prevent progression to CKD despite increasing reports demonstrating that uremic toxins are correlated with the severity of injury or mortality. This review highlights the current evidence of uremic toxin accumulation in AKI and the therapeutic value to prevent CKD progression specific to protein-bound uremic toxins (PBUTs). Full article

(This article belongs to the Special Issue Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease)

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23 pages, 1689 KiB

Open AccessReview

Extracellular Vesicles and Their Relationship with the Heart–Kidney Axis, Uremia and Peritoneal Dialysis

by Carolina Amaral Bueno Azevedo, Regiane Stafim da Cunha, Carolina Victoria Cruz Junho, Jessica Verônica da Silva, Andréa N. Moreno-Amaral, Thyago Proença de Moraes, Marcela Sorelli Carneiro-Ramos and Andréa Emilia Marques Stinghen

Toxins 2021, 13(11), 778; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13110778 - 04 Nov 2021

Cited by 8 | Viewed by 3465

Abstract

Cardiorenal syndrome (CRS) is described as primary dysfunction in the heart culminating in renal injury or vice versa. CRS can be classified into five groups, and uremic toxin (UT) accumulation is observed in all types of CRS. Protein-bound uremic toxin (PBUT) accumulation is [...] Read more.

Cardiorenal syndrome (CRS) is described as primary dysfunction in the heart culminating in renal injury or vice versa. CRS can be classified into five groups, and uremic toxin (UT) accumulation is observed in all types of CRS. Protein-bound uremic toxin (PBUT) accumulation is responsible for permanent damage to the renal tissue, and mainly occurs in CRS types 3 and 4, thus compromising renal function directly leading to a reduction in the glomerular filtration rate (GFR) and/or subsequent proteinuria. With this decrease in GFR, patients may need renal replacement therapy (RRT), such as peritoneal dialysis (PD). PD is a high-quality and home-based dialysis therapy for patients with end-stage renal disease (ESRD) and is based on the semi-permeable characteristics of the peritoneum. These patients are exposed to factors which may cause several modifications on the peritoneal membrane. The presence of UT may harm the peritoneum membrane, which in turn can lead to the formation of extracellular vesicles (EVs). EVs are released by almost all cell types and contain lipids, nucleic acids, metabolites, membrane proteins, and cytosolic components from their cell origin. Our research group previously demonstrated that the EVs can be related to endothelial dysfunction and are formed when UTs are in contact with the endothelial monolayer. In this scenario, this review explores the mechanisms of EV formation in CRS, uremia, the peritoneum, and as potential biomarkers in peritoneal dialysis. Full article

(This article belongs to the Special Issue Uremic Toxin-Mediated Mechanisms in Cardiovascular and Renal Disease)

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26 pages, 3109 KiB

Open AccessReview

Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets

by Yong Jin Lim, Nicole A. Sidor, Nicholas C. Tonial, Adrian Che and Bradley L. Urquhart

Toxins 2021, 13(2), 142; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13020142 - 13 Feb 2021

Cited by 100 | Viewed by 14695

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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15 pages, 1485 KiB

Open AccessReview

Indoxyl Sulfate, a Tubular Toxin, Contributes to the Development of Chronic Kidney Disease

by Tong-Hong Cheng, Ming-Chieh Ma, Min-Tser Liao, Cai-Mei Zheng, Kuo-Cheng Lu, Chun-Hou Liao, Yi-Chou Hou, Wen-Chih Liu and Chien-Lin Lu

Toxins 2020, 12(11), 684; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12110684 - 29 Oct 2020

Cited by 45 | Viewed by 4579

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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14 pages, 1569 KiB

Open AccessEditor’s ChoiceReview

Indoxyl Sulfate, a Uremic Endotheliotoxin

by Guillaume Lano, Stéphane Burtey and Marion Sallée

Toxins 2020, 12(4), 229; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12040229 - 05 Apr 2020

Cited by 75 | Viewed by 6083

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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