Vascular Incompetence in Dialysis Patients—Protein‐Bound Uremic Toxins and Endothelial Dysfunction

Jourde-Chiche, Noémie; Dou, Laetitia; Cérini, Claire; Dignat-George, Françoise; Brunet, Philippe

doi:10.1111/j.1525-139x.2011.00925.x

Cited by 164 publications

(147 citation statements)

References 185 publications

(234 reference statements)

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“…7 In mice with advanced CKD, we found that Notch signaling in ECs is activated by cell-cell interaction, leading to the expression of mesenchymal proteins in ECs of the AVFs. One possible trigger of Notch activation is TGF-b1 in uremic mice.…”

Section: Discussionmentioning

confidence: 85%

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Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD

Wang

Liang

Luo

et al. 2014

Journal of the American Society of Nephrology

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Neointima formation causes the failure of 60% of arteriovenous fistulas (AVFs) within 2 years. Neointimaforming mechanisms are controversial but possibly linked to excess proinflammatory responses and dysregulated Notch signaling. To identify how AVFs fail, we anastomosed the carotid artery to the internal jugular vein in normal and uremic mice and compared these findings with those in failed AVFs from patients with ESRD. Endothelial cells (ECs) of AVFs in uremic mice or patients expressed mesenchymal markers (FSP-1 and/or a-SMA) and exhibited increased expression and nuclear localization of Notch intracellular domain compared with ECs of AVFs in pair-fed control mice. Furthermore, expression of VE-Cadherin decreased, whereas expression of Notch1 and -4, Notch ligands, the downstream transcription factor of Notch, RBP-Jk, and Notch target genes increased in ECs of AVFs in uremic mice. In cultured ECs, ectopic expression of Notch ligand or treatment with TGF-b1 triggered the expression of mesenchymal markers and induced endothelial cell barrier dysfunction, both of which were blocked by Notch inhibition or RBP-Jk knockout. Furthermore, Notch-induced defects in barrier function, invasion of inflammatory cells, and neointima formation were suppressed in mice with heterozygous knockdown of endothelial-specific RBP-Jk. These results suggest that increased TGF-b1, a complication of uremia, activates Notch in endothelial cells of AVFs, leading to accelerated neointima formation and AVF failure. Suppression of Notch activation could be a strategy for improving AFV function in uremia.

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Section: Discussionmentioning

confidence: 85%

“…For example, in patients with CKD, biomarkers of endothelial dysfunction (vWf and vascular cell adhesion molecule-1) are expressed in ECs, and the capacity for endothelial repair is decreased. 7 However, the relationships among CKD-induced changes in ECs and neointima formation in AVFs are poorly defined.…”

mentioning

confidence: 99%

Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD

Wang

Liang

Luo

et al. 2014

Journal of the American Society of Nephrology

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“…Moreover, present inflammation acts as a trigger and amplifier of OS. Various uremic toxins, including homocystein, advanced glycation end products, p-cresyl sulfate, and indoxyl sulfate, directly contribute to OS through their pro-oxidant and proinflammatory actions (53).…”

Section: Osmentioning

confidence: 99%

Vascular Effects of Exercise Training in CKD

Craenenbroeck

Kouidi

et al. 2014

Clinical Journal of the American Society of Nephrology

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Cardiovascular disease remains the main cause of morbidity and mortality in patients with CKD, an observation that cannot be explained by the coexistence of traditional risk factors alone. Recently, other mechanisms, such as alterations in nitric oxide bioavailability, impaired endothelial repair mechanisms, inflammation, and oxidative stress (all characteristic in CKD), have gained much attention as mediators for the increased cardiovascular risk. Regular physical training is a valuable nonpharmacological intervention for primary and secondary prevention of cardiovascular disease. Likewise, the benefits of exercise training on exercise capacity and quality of life are increasingly recognized in patients with CKD. Furthermore, exercise training could also influence potential reversible mechanisms involved in atherosclerosis and arteriosclerosis. After discussing briefly the general concepts of vascular disease in CKD, this review provides an overview of the current evidence for the effects of exercise training at both clinical and preclinical levels. It concludes with some practical considerations on exercise training in this specific patient group.

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“…2,3 Serum levels of some uremic solutes are correlated with cardiovascular events and mortality in patients with CKD. 4 Uremic solutes have been identified as inducers of oxidative stress, inflammation, and endothelial dysfunction. [4][5][6] Indole-3 acetic acid (IAA) is a protein-bound uremic solute from tryptophan metabolism.…”

mentioning

confidence: 99%

“…4 Uremic solutes have been identified as inducers of oxidative stress, inflammation, and endothelial dysfunction. [4][5][6] Indole-3 acetic acid (IAA) is a protein-bound uremic solute from tryptophan metabolism. 7 Its serum level is increased in patients with CKD; 3 the mean uremic concentration is about 5 mM, 8 and the highest concentration is 50 mM.…”

mentioning

confidence: 99%

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

Dou

Sallée

Cérini

et al. 2015

Journal of the American Society of Nephrology

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In CKD, uremic solutes may induce endothelial dysfunction, inflammation, and oxidative stress, leading to increased cardiovascular risk. We investigated whether the uremic solute indole-3 acetic acid (IAA) predicts clinical outcomes in patients with CKD and has prooxidant and proinflammatory effects. We studied 120 patients with CKD. During the median study period of 966 days, 29 patients died and 35 experienced a major cardiovascular event. Kaplan-Meier analysis revealed that mortality and cardiovascular events were significantly higher in the higher IAA group (IAA.3.73 mM) than in the lower IAA group (IAA,3.73 mM). Multivariate Cox regression analysis demonstrated that serum IAA was a significant predictor of mortality and cardiovascular events after adjustments for age and sex; cholesterol, systolic BP, and smoking; C-reactive protein, phosphate, body mass index, and albumin; diastolic BP and history of cardiovascular disease; and uremic toxins p-cresyl sulfate and indoxyl sulfate. Notably, IAA level remained predictive of mortality when adjusted for CKD stage. IAA levels were positively correlated with markers of inflammation and oxidative stress: C-reactive protein and malondialdehyde, respectively. In cultured human endothelial cells, IAA activated an inflammatory nongenomic aryl hydrocarbon receptor (AhR)/p38MAPK/NF-kB pathway that induced the proinflammatory enzyme cyclooxygenase-2. Additionally, IAA increased production of endothelial reactive oxygen species. In conclusion, serum IAA may be an independent predictor of mortality and cardiovascular events in patients with CKD. In vitro, IAA induces endothelial inflammation and oxidative stress and activates an inflammatory AhR/p38MAPK/NF-kB pathway.

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Vascular Incompetence in Dialysis Patients—Protein‐Bound Uremic Toxins and Endothelial Dysfunction

Cited by 164 publications

References 185 publications

Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD

Blocking Notch in Endothelial Cells Prevents Arteriovenous Fistula Failure Despite CKD

Vascular Effects of Exercise Training in CKD

The Cardiovascular Effect of the Uremic Solute Indole-3 Acetic Acid

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