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Abstract: FR-PO484

Protein Bound Uremic Toxins Promote Vascular Calcification by Glucose Mediated Activation of Inflammation and Coagulation Pathways

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Opdebeeck, Britt, University of Antwerp, Wilrijk, Belgium
  • De maré, Annelies, University of Antwerp, Wilryk, antwerp, Belgium
  • Meijers, Bjorn, University Hospitals Leuven, Leuven, Belgium
  • Verhulst, Anja, University of Antwerp, Wilryk, antwerp, Belgium
  • Evenepoel, Pieter, University Hospitals Leuven, Leuven, Belgium
  • D'Haese, Patrick C., University Antwerp, Edegem, Belgium
  • Neven, Ellen, University of Antwerp, Wilryk, antwerp, Belgium
Background

Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). We aimed to provide direct evidence for a role of these toxins in CKD-related vascular calcification.

Methods

To induce CKD, rats were orally dosed with adenine sulfate for 10 days and continuously exposed to either vehicle, IS or PCS (150 mg/kg/day) until 7 weeks after CKD induction. Vascular calcification was assessed by measurement of arterial calcium content and through histochemical evaluation of Von Kossa stained sections. Quantitative mass spectrometric proteomics was further employed to investigate the mechanistic pathways underlying IS and PCS-mediated vascular calcification.

Results

IS and PCS exposure did not worsen renal function, fibrosis, or inflammation. Calcification in the aorta, carotid and femoral arteries was significantly increased by exposure to both toxins, for which serum levels similar to CKD patients were reached. Arterial calcification was not associated with changes in bone metabolism inherent to CKD. Unbiased proteomic analyses of arterial samples coupled to functional bioinformatics annotation analysis revealed that calcification events were likely associated with acute phase response signaling, coagulation and glucometabolic signaling pathways, while escape from calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Further metabolic linkage to these pathways also revealed that IS/PCS exposure engendered a pro-diabetic state, evidenced by elevated resting glucose and reduced glucose transporter (Glut1) transcript expression.

Conclusion

We demonstrate that both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways in the arterial wall which was strongly associated with impaired glucose homeostasis.

Funding

  • Government Support - Non-U.S.