P-cresol, but not p-cresylsulphate, disrupts endothelial progenitor cell function in vitro

Zhu, Jinzhou; Zhang, Jing; Yang, Ke; Du, Rong; Jing, Yajun; Lü, Lin; Zhang, Ruiyan

doi:10.1093/ndt/gfs382

Cited by 24 publications

(19 citation statements)

References 49 publications

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“…48 All studies evaluating indoxyl sulfate showed a negative (toxic) effect (Table 3), except the study by Odamaki et al, 52 which showed an increase of hepatocyte albumin production in the presence of indoxyl sulfate. Four studies on p-cresyl sulfate [53][54][55][56] and one study on indoxyl sulfate 55 showed no significant changes (data not shown).…”

Section: Resultsmentioning

confidence: 99%

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder

Schepers

Pletinck

et al. 2014

Journal of the American Society of Nephrology

575

463

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A growing number of publications supports a biologic effect of the protein-bound uremic retention solutes indoxyl sulfate and p-cresyl sulfate. However, the use of unrealistically high free concentrations of these compounds and/or inappropriately low albumin concentrations may blur the interpretation of these results. Here, we performed a systematic review, selecting only studies in which, depending on the albumin concentration, real or extrapolated free concentrations of indoxyl sulfate and p-cresyl sulfate remained in the uremic range. The 27 studies retrieved comprised in vitro and animal studies. A quality score was developed, giving 1 point for each of the following criteria: six or more experiments, confirmation by more than one experimental approach, neutralization of the biologic effect by counteractive reagents or antibodies, use of a real-life model, and use of dose-response analyses in vitro and/or animal studies. The overall average score was 3 of 5 points, with five studies scoring 5 of 5 points and six studies scoring 4 of 5 points, highlighting the superior quality of a substantial number of the retrieved studies. In the 11 highest scoring studies, most functional deteriorations were related to uremic cardiovascular disease and kidney damage. We conclude that our systematic approach allowed the retrieval of methodologically correct studies unbiased by erroneous conditions related to albumin binding. Our data seem to confirm the toxicity of indoxyl sulfate and p-cresyl sulfate and support their roles in vascular and renal disease progression.

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Section: Resultsmentioning

confidence: 99%

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Vanholder

Schepers

Pletinck

et al. 2014

Journal of the American Society of Nephrology

575

463

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“…; Zhu et al . ). The accumulation of these compounds represents a serious clinical problem in CKD patients, as their removal by conventional haemodialysis is low because they do not diffuse through the dialysis membrane (Jourde‐Chiche et al .…”

Section: Discussionmentioning

confidence: 97%

Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

García-Jérez

Luengo

Carracedo

et al. 2014

The Journal of Physiology

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Key pointsr Patients with chronic kidney disease have a higher risk of developing cardiovascular diseases than the general population. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which have poor clearance by conventional dialysis.r Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity and in this study we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia.r For the first time, we demonstrate the implication of ILK in the protection against endothelial cell damage (inhibition of proliferation, toxicity, oxidative stress and programed cell death) induced by uraemic serum from chronic kidney disease patients and uraemic toxins.r This molecular mechanism may have clinical relevance because it highlights the importance of maintaining high levels of ILK activity to help preserve endothelial integrity, at least in early stages of chronic kidney disease.Abstract Patients with chronic kidney disease (CKD) have a higher risk of developing cardiovascular diseases. Their vascular endothelium is dysfunctional, among other things, because it is permanently exposed to uraemic toxins, several of which, mostly protein-bound compounds such as indoxyl sulfate (IS) and p-cresyl sulphate, having poor clearance by conventional dialysis, induce endothelial toxicity. However, the molecular mechanism by which uraemic toxins regulate early stages of endothelial dysfunction remains unclear. Recent studies have demonstrated the important role of integrin-linked kinase (ILK) in the maintenance of endothelial integrity. In this study, we investigate the involvement of ILK in the mechanism underlying vascular endothelial damage that occurs in uraemia. First, we show that incubation of EA.hy926 cells with human uraemic serum from CKD patients upregulates ILK activity. This ILK activation also occurs when the cells are exposed to IS (25-100 μg ml −1 ), p-cresol (10-100 μg ml −1 ) or both combined, compared to human serum control. Next, we observed that high doses of both toxins together induce a slight decrease in cell proliferation and increase apoptosis and reactive oxygen species production. Interestingly, these toxic effects displayed a strong increase when the ILK protein is knocked down by small interfering RNA, even at low doses of uraemic toxins. Abrogation of AKT has demonstrated the ILK/AKT signalling pathway involved in these processes. This study has demonstrated the implication of ILK in the protection against endothelial cell damage induced by uraemic toxins, a molecular mechanism that could play a protective role in the early stages of endothelial dysfunction observed in uraemic patients.

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“…By providing an alternative route for flow, collateral circulation in the heart can limit ischemic injury and improve myocardial function, thus improving survival of patients with stable angina and chronic total occlusion (CTO) . Angiogenesis involves several important steps, including activation, migration, and proliferation of differentiated endothelial cells; however, abnormal accumulation of certain uremic toxins and metabolites has been demonstrated to inhibit these angiogenic processes …”

Section: Introductionmentioning

confidence: 99%

Cyanate‐Impaired Angiogenesis: Association With Poor Coronary Collateral Growth in Patients With Stable Angina and Chronic Total Occlusion

Sun

Yang

Mao

et al. 2016

JAHA

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BackgroundCyanate has recently gained attention for its role in the pathogenesis of vascular injury. Nonetheless, the effect of cyanate on angiogenesis remains unclear.Methods and ResultsIn this study, we demonstrated that oral administration of cyanate impaired blood perfusion recovery in a mouse hind‐limb ischemia model. A reduction in blood perfusion recovery at day 21 was observed in the ischemic tissue of cyanate‐treated mice. Likewise, there were fewer capillaries in the ischemic hind‐limb tissue of cyanate‐exposed mice. Our in vitro study showed that cyanate, together with its carbamylated products, inhibited the migration, proliferation, and tube‐formation abilities of endothelial cells. Further research revealed that cyanate regulated angiogenesis partly by interrupting the vascular endothelial growth factor receptor 2/phosphatidylinositol 3‐kinase/Akt pathway. The serum concentrations of homocitrulline, a marker of cyanate exposure, were determined in 117 patients with stable angina and chronic total occlusion. Consistent with the antiangiogenic role of cyanate, homocitrulline levels were increased in patients with poor coronary collateralization (n=58) compared with those with high collateralization (n=59; 21.09±13.08 versus 15.54±9.02 ng/mL, P=0.009). In addition, elevated homocitrulline concentration was a strong predictor of poor coronary collateral growth.ConclusionsImpaired angiogenesis induced by cyanate might contribute to poor coronary collateral growth.

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P-cresol, but not p-cresylsulphate, disrupts endothelial progenitor cell function in vitro

Abstract: Our data demonstrate that pC and pCS have different effects on EPC function. Since there is a dearth of data that have focused on the toxicity of pCS, further research should be performed to determine the exact biological toxicity of pCS on the cardiovascular system.

Cited by 24 publications

References 49 publications

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

The Uremic Toxicity of Indoxyl Sulfate and p-Cresyl Sulfate

Effect of uraemia on endothelial cell damage is mediated by the integrin linked kinase pathway

Cyanate‐Impaired Angiogenesis: Association With Poor Coronary Collateral Growth in Patients With Stable Angina and Chronic Total Occlusion

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