Abstract: FR-PO184

CKD and Arterial Thrombosis: Role of the Receptor for Advanced Glycation End-Products (RAGE)

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction

Authors

  • Ortillon, Jeremy, CNRS UMR URCA 7369, Reims, France
  • Toure, Fatouma, CHU and UMR CNRS URCA 7369 , Reims, France
  • Hézard, Nathalie, EA 3801 HERVI, REIMS, France
  • Belmokhtar, Karim, CNRS UMR URCA 7369, Reims, France
  • Charlotte, Kawecki, INSERM U1176, le Kremlin-Bicêtre, France
  • Terryn, Christine, Universite de Reims Champagne Ardenne, REIMS, France
  • Schmidt, Ann Marie, NYU Medical Center, New York, New York, United States
  • Maurice, Pascal, UMR CNRS/URCA 7369, Reims, France
  • Nguyen, Philippe V, University of Reims, REIMS, France
  • Rieu, Philippe, CHU and UMR CNRS URCA 7369 , Reims, France
Background

Chronic kidney disease (CKD) is associated with extensive vascular wall remodelling and vasculopathy as well as accumulation of uremic toxins. Among these toxins, advanced glycation end-products (AGEs) interact with the receptor for advanced glycation end-products (RAGE). In this study, we aimed to analyze the impact of CKD on arterial thrombosis and the potential role of RAGE in this process.

Methods

We used a mouse model of uremic vasculopathy consisting in a 2-step 5/6 nephrectomy. Four groups of animals were studied: Apoe-/- mice sham operated (n=12) or uremic (n=10) and Apoe-/-/Ager-/- (= Apoe-/-RAGE -/-) mice sham operated (n=11) or uremic (n=15). Twelve weeks after surgery: 1) arterial thrombosis was induced by ferric chloride application on the carotid artery and complete carotid occlusion time was measured, 2) platelet function was analysed in whole blood and in platelet rich plasma (PRP).

Results

In-vivo, uremia significantly accelerates the occlusion time in Apoe-/- mice (9.2 ±1,1min vs 11.1 ±0,6 min, p<0.01) compared to sham animals. IIn contrast, uremia had no effect on Apoe-/-/Ager-/- mice carotid occlusion time (14,5 ±2,3 min, vs 13 ±1,5 min in sham, NS). Moreover occlusion time of the uremic Apoe-/- mice was significantly accelerated compared to uremic Apoe-/- /Ager-/- mice (p<0,0001). Ex-vivo, agonist-induced platelet aggregation in whole blood was significantly increased in uremic condition in both Apoe--/- and Apoe-/- /Ager-/- mice. In PRP, aggregation of uremic Apoe-/- mice platelets was significantly increased compared to that of uremic Apoe-/-/Ager-/- mice. In agreement, agonist induced expression of activated integrin αIIbβ3 and P-selectin were both significantly increased at the surface of Apoe--/- uremic platelets compared to 1) Apoe-/- sham platelets and to 2) Apoe-/-/Ager-/- platelets (uremic & sham).

Conclusion

In this murine model of thrombosis we report that uremia accelerates arterial thrombus formation and induces platelets hyperreactivity. We found that Ager deletion had a protective role on uremia-induced arterial thrombosis, and in uremia-induced platelet hyperreactivity. We suggest that RAGE signaling may be involved in CKD-induced atherothrombosis.

Funding

  • Government Support - Non-U.S.