Receptor for Advanced Glycation End Products is Involved in Platelet Hyperactivation and Arterial Thrombosis during

Jérémy Ortillon1, Nathalie Hézard2, Karim Belmokhtar1

  • 1UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 "Matrix Aging and Vascular Remodelling," Université de Reims Champagne Ardenne, Reims, France.

Abstract

Insights

Chronic kidney disease (CKD) accelerates arterial thrombosis by causing platelet hyperactivation. Blocking the receptor for AGEs (RAGE) protects against this effect, suggesting RAGE is key in CKD-related vascular events.

Area of Science:

  • Cardiovascular Science
  • Nephrology
  • Thrombosis Research

Background:

  • Chronic kidney disease (CKD) is linked to high cardiovascular mortality, partly due to vascular lesions and thrombotic events.
  • Uremic toxins, such as advanced glycation end products (AGEs) and S100 proteins, accumulate in CKD and can activate the receptor for AGEs (RAGE).

Purpose of the Study:

  • To investigate the impact of CKD on platelet function and arterial thrombosis.
  • To explore the role of the RAGE pathway in CKD-associated thrombotic complications.

Main Methods:

  • Murine model of CKD was established 12 weeks prior to analysis.
  • Platelet function and carotid artery occlusion times were assessed in sham-operated, CKD, apolipoprotein E knockout (Apoe-/-), and RAGE/Apoe double knockout (Apoe-/-/Ager-/-) mice.

Main Results:

  • CKD induced platelet hyperactivation in Apoe-/- mice, but not in washed platelets, suggesting a role for plasma factors.
  • Preincubation with AGEs or S100 proteins led to RAGE-mediated platelet hyperactivation.
  • CKD significantly shortened carotid artery occlusion times in Apoe-/- mice, an effect abolished in Apoe-/-/Ager-/- mice.

Conclusions:

  • CKD promotes platelet hyperactivation and accelerates arterial thrombus formation in a murine model.
  • Deletion of RAGE confers a protective effect against CKD-induced arterial thrombosis.
  • RAGE ligands binding to RAGE are implicated in the pathogenesis of CKD-associated arterial thrombosis.

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