Britt Opdebeeck1, Stuart Maudsley2,3, Abdelkrim Azmi3, Annelies De Maré1, Wout De Leger4, Bjorn Meijers5,6, Anja Verhulst1, Pieter Evenepoel5,6, Patrick C D'Haese7, Ellen Neven1. 1. Laboratory of Pathophysiology, Department of Biomedical Sciences. 2. Receptor Biology Lab, Department of Biomedical Sciences, and. 3. Translational Neurobiology Group, Flanders Institute of Biotechnology Center for Molecular Neurology, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. 4. Division of Molecular Design and Synthesis, Department of Chemistry and. 5. Division of Internal Medicine, Nephrology, University Hospitals Leuven, Leuven, Belgium. 6. Laboratory of Nephrology, Department of Immunology and Microbiology, Catholic University of Leuven, Leuven, Belgium; and. 7. Laboratory of Pathophysiology, Department of Biomedical Sciences, Patrick.dhaese@uantwerpen.be.
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.
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.
Authors: Sam Hobson; Henriette de Loor; Karolina Kublickiene; Joachim Beige; Pieter Evenepoel; Peter Stenvinkel; Thomas Ebert Journal: Toxins (Basel) Date: 2022-06-16 Impact factor: 5.075
Authors: Tibor I Krisko; Hayley T Nicholls; Curtis J Bare; Corey D Holman; Gregory G Putzel; Robert S Jansen; Natalie Sun; Kyu Y Rhee; Alexander S Banks; David E Cohen Journal: Cell Metab Date: 2020-02-20 Impact factor: 27.287