Thromb Haemost 2020; 120(09): 1300-1312
DOI: 10.1055/s-0040-1714101
Cellular Haemostasis and Platelets

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

Jérémy Ortillon
1  UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 “Matrix Aging and Vascular Remodelling,” Université de Reims Champagne Ardenne, Reims, France
,
Nathalie Hézard
2  Hémostase et Remodelage Vasculaire Post-Ischémique, Laboratoire d'Hématologie, Faculté de Médecine & CHU Reims, Hôpital Robert Debré, Reims, France
,
Karim Belmokhtar
1  UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 “Matrix Aging and Vascular Remodelling,” Université de Reims Champagne Ardenne, Reims, France
,
Charlotte Kawecki
1  UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 “Matrix Aging and Vascular Remodelling,” Université de Reims Champagne Ardenne, Reims, France
,
Christine Terryn
3  PICT Platform, Université de Reims Champagne Ardenne, Reims, France
,
Guenter Fritz
4  Institute of Neuropathology, Neurozentrum, University of Freiburg, Freiburg, Germany
,
Alexandre Kauskot
5  HITh, UMR_S 1176, INSERM Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
,
Ann Marie Schmidt
6  Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, New York, United States
,
Philippe Rieu
1  UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 “Matrix Aging and Vascular Remodelling,” Université de Reims Champagne Ardenne, Reims, France
7  Division of Nephrology, CHU Reims, Reims, France
,
Philippe Nguyen
2  Hémostase et Remodelage Vasculaire Post-Ischémique, Laboratoire d'Hématologie, Faculté de Médecine & CHU Reims, Hôpital Robert Debré, Reims, France
,
1  UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 “Matrix Aging and Vascular Remodelling,” Université de Reims Champagne Ardenne, Reims, France
,
Fatouma Touré
1  UMR CNRS 7369 Matrice Extracellulaire et Dynamique Cellulaire (MEDyC), Team 2 “Matrix Aging and Vascular Remodelling,” Université de Reims Champagne Ardenne, Reims, France
8  Division of Nephrology, CHU Limoges, Limoges, France
› Author Affiliations
Funding This work was supported by funding from CNRS, URCA. F.T. was recipient of a grant from the Société Francophone de Nephrologie Dialyse Transplantation (SFNDT). C.K. was recipient of a scholarship from the Nouvelle Société Francophone d'Athérosclérose (NSFA).

Abstract

Background Chronic kidney disease (CKD) is associated with a high cardiovascular mortality due to increased rates of vascular lesions and thrombotic events, as well as serum accumulation of uremic toxins. A subgroup of these toxins (advanced glycation end products [AGEs] and S100 proteins) can interact with the receptor for AGEs (RAGE). In this study, we analyzed the impact of CKD on platelet function and arterial thrombosis, and the potential role of RAGE in this process.

Methods Twelve weeks after induction of CKD in mice, platelet function and time to complete carotid artery occlusion were analyzed in four groups of animals (sham-operated, CKD, apolipoprotein E [Apoe]−/−, and Apoe−/−/Ager−/− mice).

Results Analysis of platelet function from whole blood and platelet-rich plasma showed hyperactivation of platelets only in CKD Apoe−/− mice. There was no difference when experiments were done on washed platelets. However, preincubation of such platelets with AGEs or S100 proteins induced RAGE-mediated platelet hyperactivation. In vivo, CKD significantly reduced carotid occlusion times of Apoe−/− mice (9.2 ± 1.1 vs. 11.1 ± 0.6 minutes for sham, p < 0.01). In contrast, CKD had no effect on occlusion times in Apoe−/−/Ager−/− mice. Moreover, carotid occlusion in Apoe−/− CKD mice occurred significantly faster than in Apoe−/−/Ager−/− CKD mice (p < 0.0001).

Conclusion Our results show that CKD induces platelet hyperactivation, accelerates thrombus formation in a murine model of arterial thrombosis, and that RAGE deletion has a protective role. We propose that RAGE ligands binding to RAGE is involved in CKD-induced arterial thrombosis.

Authors' Contributions

F.T., P.M. N.H., P.N., and J.O. designed the experiments. J.O. and K.B. realized the surgery of mouse CKD model. J.O. and C.K. realized the animal model of arterial thrombosis. J.O. and N.H. worked together for analysis of platelet functions ex vivo. C.T. provided help and material for monitoring arterial thrombosis in vivo. A.K. and P.R. participated to scientific discussions. J.O. and F.T. wrote the first draft of the manuscript. F.T., P.M., and P.N. wrote the final version of the manuscript.


Supplementary Material



Publication History

Received: 07 April 2020

Accepted: 30 May 2020

Publication Date:
29 July 2020 (online)

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