Dataset Information

Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance.

ABSTRACT: BACKGROUND:Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with CKD. However, direct evidence for a role of these toxins in CKD-related vascular calcification has not been reported. METHODS:To study early and late vascular alterations by toxin exposure, we exposed CKD rats to vehicle, IS (150 mg/kg per day), or PCS (150 mg/kg per day) for either 4 days (short-term exposure) or 7 weeks (long-term exposure). We also performed unbiased proteomic analyses of arterial samples coupled to functional bioinformatic annotation analyses to investigate molecular signaling events associated with toxin-mediated arterial calcification. RESULTS:Long-term exposure to either toxin at serum levels similar to those experienced by patients with CKD significantly increased calcification in the aorta and peripheral arteries. Our analyses revealed an association between calcification events, acute-phase response signaling, and coagulation and glucometabolic signaling pathways, whereas escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Additional metabolic linkage to these pathways revealed that IS and PCS exposure engendered a prodiabetic state evidenced by elevated resting glucose and reduced GLUT1 expression. Short-term exposure to IS and PCS (before calcification had been established) showed activation of inflammation and coagulation signaling pathways in the aorta, demonstrating that these signaling pathways are causally implicated in toxin-induced arterial calcification. CONCLUSIONS:In CKD, both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways and were strongly associated with impaired glucose homeostasis.

SUBMITTER: Opdebeeck B

PROVIDER: S-EPMC6493976 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance.

Opdebeeck Britt B Maudsley Stuart S Azmi Abdelkrim A De Maré Annelies A De Leger Wout W Meijers Bjorn B Verhulst Anja A Evenepoel Pieter P D'Haese Patrick C PC Neven Ellen E

Journal of the American Society of Nephrology : JASN 20190402 5

<h4>Background</h4>Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with CKD. However, direct evidence for a role of these toxins in CKD-related vascular calcification has not been reported.<h4>Methods</h4>To study early and late vascular alterations by toxin exposure, we exposed CKD rats to vehicle, IS (150 mg/kg per day), or PCS (150 mg/kg per day) for either 4 days (short-term exposure) or ...[more]

PMID: 30940651

Similar Datasets

Project description:Background and objectivesp-Cresyl sulfate and indoxyl sulfate contribute to cardiovascular disease and progression of renal disease. Renal clearance of both solutes mainly depends on tubular secretion, and serum concentrations are widely dispersed for any given stage of CKD. From this information, it is inferred that estimated GFR is not a suitable proxy of the clearance of these solutes. Formal clearance studies have, however, not been performed to date.Design, setting, participants, & measurementsThis study analyzed renal clearances of p-cresyl sulfate and indoxyl sulfate in the Leuven CKD cohort (NCT00441623; inclusion between November of 2005 and September of 2006) and explored their relationship with estimated GFR. Multivariate linear regression models were built to evaluate contributions of estimated GFR, demographics, and generation rates to p-cresyl sulfate and indoxyl sulfate serum concentrations.ResultsRenal clearances were analyzed in 203 patients with CKD stages 1-5. Indoxyl sulfate clearances (median=17.7, interquartile range=9.4-33.2 ml/min) exceeded p-cresyl sulfate clearances (median=6.8, interquartile range=3.4-12.0 ml/min) by about threefold. A linear relationship was observed between estimated GFR and clearances of p-cresyl sulfate (R(2)=0.50, P<0.001) and indoxyl sulfate (R(2)=0.55, P<0.001). In multivariate regression, p-cresyl sulfate concentrations were associated (R(2)=0.75) with estimated GFR and generation rate (both P<0.001). Indoxyl sulfate concentrations were associated (R(2)=0.74) with estimated GFR, generation rate (both P<0.001), age (P<0.05), and sex (P<0.05).ConclusionsEstimated GFR provides an acceptable estimate of renal clearance of p-cresyl sulfate and indoxyl sulfate. Remarkably, clearances of indoxyl sulfate exceed clearances of p-cresyl sulfate by approximately threefold, suggesting substantial differences between tubular transporter affinities and/or involvement of separate transporter systems for p-cresyl sulfate and indoxyl sulfate.

Dataset Information

Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance.

Publications

Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets