Vascular toxicity of urea, a new “old player” in the pathogenesis of chronic renal failure induced cardiovascular diseases

Giardino, Ida; D’Apolito, Maria; Brownlee, Michael; Maffione, Angela Bruna; Colia, Anna Laura; Sacco, Michele; Ferrara, Pietro; Pettoello-Mantovani, Massimo

doi:10.5152/turkpediatriars.2017.6314

Cited by 6 publications

(5 citation statements)

References 50 publications

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“…Urea and creatinine are typical uremic toxins, most commonly used to evaluate CKD patients in clinics (Lau and Vaziri, 2017 ). Urea substantially contribute to the progression atherosclerosis by inducing endothelial dysfunction, endothelial progenitor cells senescence, and apoptosis of vascular smooth muscle cells (Giardino et al, 2017 ). Uric acid is known as an important uremic toxin contributing to CKD progression (Gustafsson and Unwin, 2013 ; Tsai et al, 2017 ) and increasing risk of cardiovascular mortality in CKD patients (Luo et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System

Jang

Cho

Zhou

et al. 2021

Front. Cell Dev. Biol.

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Background: Cardiovascular complications are the leading cause of mortality in patients with chronic kidney disease (CKD). Uremic vasculopathy plays a crucial role in facilitating the progression of cardiovascular complications in advanced CKD. However, the improvement of conventional research methods could provide further insights into CKD.Objectives: In this study, we aimed to develop a novel model of uremic vasculopathy as a potential drug screening system.Methods and Results: The effects of uremic serum and different combinations of uremic toxins on induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) of a normal control and a CKD patient were investigated using several functional assays. We found that a mixture of uremic toxins composed of high urea, creatinine, uric acid, and indoxyl sulfate exerted deleterious effects on normal control iPSC-ECs that were comparable to uremic serum by increasing reactive oxygen species and apoptosis, as well as suppression of tube formation. Additional characterization revealed a potential involvement of dysregulated TGF-β signaling as treatment with either losartan or TGF-β inhibitors led to the attenuation of adverse effects induced by uremic toxins. Importantly, impaired wound healing potential seen in CKD patient-specific iPSC-ECs was rescued by treatment with losartan and TGF-β inhibitors.Conclusion: Our study demonstrated that simplified uremic toxin mixtures can simulate the uremic micromilieu reproducibly and CKD patient-specific iPSC-ECs can potentially recapitulate susceptibility to uremic vasculopathy. This novel model of uremic vasculopathy may provide a new research tool as a drug screening system.

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Section: Discussionmentioning

confidence: 99%

Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System

Jang

Cho

Zhou

et al. 2021

Front. Cell Dev. Biol.

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“…Similar to glucose, urea at disease relevant concentrations has a direct vascular toxicity [ 24 , 25 ], inducing endothelial dysfunction by increasing intracellular ROS production through the activation of both mitochondrial and cytosolic ROS generating mechanisms [ 11 , 12 ]. In the present report, we have shown that transient exposure to 20 mM urea induces ROS production in human aortic endothelial cells that persists for days after urea is removed.…”

Section: Discussionmentioning

confidence: 99%

Urea Memory: Transient Cell Exposure to Urea Causes Persistent Mitochondrial ROS Production and Endothelial Dysfunction

D’Apolito

Colia

Manca

et al. 2018

Toxins

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Urea at post-dialysis levels induces increased ROS in a number of cell types. The aim of this study was to determine whether urea-induced production of ROS remains elevated after urea is no longer present, and, if it does, to characterize its origin and effects. Human arterial endothelial cells were incubated with 20 mM urea for two days, and then cells were incubated for an additional two days in medium alone. Maximal ROS levels induced by initial urea continued at the same level despite urea being absent. These effects were prevented by either MnSOD expression or by Nox1/4 inhibition with GKT13781. Sustained urea-induced ROS caused a persistent reduction in mtDNA copy number and electron transport chain transcripts, a reduction in transcription of mitochondrial fusion proteins, an increase in mitochondrial fission proteins, and persistent expression of endothelial inflammatory markers. The SOD-catalase mimetic MnTBAP reversed each of these. These results suggest that persistent increases in ROS after cells are no long exposed to urea may play a major role in continued kidney damage and functional decline despite reduction of urea levels after dialysis.

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“…The combination of ADMA and indoxyl sulfate (IxS) is involved in the increased expression in aortic cells of senescence molecules, such as senescence-associated betagalactosidase (SA-β-gal). 16 Urea, a product of protein metabolism, at physiologically relevant levels, increases ROS production in endothelial progenitor cells (EPCs) 17 . In addition, urea also decreases the number of EPCs and induces senescence in remaining EPCs 17 .…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

“…16 Urea, a product of protein metabolism, at physiologically relevant levels, increases ROS production in endothelial progenitor cells (EPCs) 17 . In addition, urea also decreases the number of EPCs and induces senescence in remaining EPCs 17 .…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

Uremic Toxins and Cardiovascular System

Glorieux

Vanholder

2021

Cardiology Clinics

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Vascular toxicity of urea, a new “old player” in the pathogenesis of chronic renal failure induced cardiovascular diseases

Cited by 6 publications

References 50 publications

Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System

Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System

Urea Memory: Transient Cell Exposure to Urea Causes Persistent Mitochondrial ROS Production and Endothelial Dysfunction

Uremic Toxins and Cardiovascular System

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