Receptor for Advanced Glycation End Products is Involved in Platelet Hyperactivation and Arterial Thrombosis during Chronic Kidney DiseaseFunding 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).
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.
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.
Received: 07 April 2020
Accepted: 30 May 2020
29 July 2020 (online)
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Stuttgart · New York
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