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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
,
Pascal Maurice 
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
› Institutsangaben 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).
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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.

Keywords

chronic kidney disease - RAGE - platelets - arterial thrombosis - uremic toxins

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



Publikationsverlauf

Eingereicht: 07. April 2020

Angenommen: 30. Mai 2020

Artikel online veröffentlicht:
29. Juli 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic renal failure. J Am Soc Nephrol 1999; 10 (07) 1606-1615
    CrossrefPubMedGoogle Scholar
  • 2 Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351 (13) 1296-1305
    CrossrefPubMedGoogle Scholar
  • 3 Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lameire N. European Uremic Toxin Work Group. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant 2005; 20 (06) 1048-1056
    CrossrefPubMedGoogle Scholar
  • 4 Drüeke TB, Massy ZA. Atherosclerosis in CKD: differences from the general population. Nat Rev Nephrol 2010; 6 (12) 723-735
    CrossrefPubMedGoogle Scholar
  • 5 Fort J. Chronic renal failure: a cardiovascular risk factor. Kidney Int Suppl 2005; ••• (99) S25-S29
    CrossrefPubMedGoogle Scholar
  • 6 London GM, Marchais SJ, Guérin AP, Métivier F. Arteriosclerosis, vascular calcifications and cardiovascular disease in uremia. Curr Opin Nephrol Hypertens 2005; 14 (06) 525-531
    CrossrefPubMedGoogle Scholar
  • 7 Landray MJ, Wheeler DC, Lip GY. , et al. Inflammation, endothelial dysfunction, and platelet activation in patients with chronic kidney disease: the Chronic Renal Impairment in Birmingham (CRIB) study. Am J Kidney Dis 2004; 43 (02) 244-253
    CrossrefPubMedGoogle Scholar
  • 8 Vanholder R, De Smet R, Glorieux G. , et al; European Uremic Toxin Work Group (EUTox). Review on uremic toxins: classification, concentration, and interindividual variability. Kidney Int 2003; 63 (05) 1934-1943
    CrossrefPubMedGoogle Scholar
  • 9 Brunet P, Gondouin B, Duval-Sabatier A. , et al. Does uremia cause vascular dysfunction?. Kidney Blood Press Res 2011; 34 (04) 284-290
    CrossrefPubMedGoogle Scholar
  • 10 Jourde-Chiche N, Dou L, Cerini C, Dignat-George F, Brunet P. Vascular incompetence in dialysis patients--protein-bound uremic toxins and endothelial dysfunction. Semin Dial 2011; 24 (03) 327-337
    CrossrefPubMedGoogle Scholar
  • 11 Karbowska M, Kaminski TW, Znorko B. , et al. Indoxyl sulfate promotes arterial thrombosis in rat model via increased levels of complex TF/VII, PAI-1, platelet activation as well as decreased contents of SIRT1 and SIRT3. Front Physiol 2018; 9: 1623
    CrossrefPubMedGoogle Scholar
  • 12 Holy EW, Akhmedov A, Speer T. , et al. Carbamylated low-density lipoproteins induce a prothrombotic state via LOX-1: impact on arterial thrombus formation in vivo. J Am Coll Cardiol 2016; 68 (15) 1664-1676
    CrossrefPubMedGoogle Scholar
  • 13 Maillard LC. Action des acides aminés sur les sucres; formation des mélanoïdes par voie méthodiques. C R Acad Sci 1912; 154: 66-68
    PubMedGoogle Scholar
  • 14 Schmidt AM, Hori O, Chen JX. , et al. Advanced glycation endproducts interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice. A potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest 1995; 96 (03) 1395-1403
    CrossrefPubMedGoogle Scholar
  • 15 Schmidt AM, Yan SD, Yan SF, Stern DM. The multiligand receptor RAGE as a progression factor amplifying immune and inflammatory responses. J Clin Invest 2001; 108 (07) 949-955
    CrossrefPubMedGoogle Scholar
  • 16 Koch M, Chitayat S, Dattilo BM. , et al. Structural basis for ligand recognition and activation of RAGE. Structure 2010; 18 (10) 1342-1352
    CrossrefPubMedGoogle Scholar
  • 17 Goury A, Meghraoui-Kheddar A, Belmokhtar K. , et al. Deletion of receptor for advanced glycation end products exacerbates lymphoproliferative syndrome and lupus nephritis in B6-MRL Fas LPR/J mice. J Immunol 2015; 194 (08) 3612-3622
    CrossrefPubMedGoogle Scholar
  • 18 Rai V, Touré F, Chitayat S. , et al. Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling. J Exp Med 2012; 209 (13) 2339-2350
    CrossrefPubMedGoogle Scholar
  • 19 Belmokhtar K, Robert T, Ortillon J. , et al. Signaling of serum amyloid A through receptor for advanced glycation end products as a possible mechanism for uremia-related atherosclerosis. Arterioscler Thromb Vasc Biol 2016; 36 (05) 800-809
    CrossrefPubMedGoogle Scholar
  • 20 Gawdzik J, Mathew L, Kim G, Puri TS, Hofmann Bowman MA. Vascular remodeling and arterial calcification are directly mediated by S100A12 (EN-RAGE) in chronic kidney disease. Am J Nephrol 2011; 33 (03) 250-259
    CrossrefPubMedGoogle Scholar
  • 21 Xu B, Chibber R, Ruggiero D, Kohner E, Ritter J, Ferro A. Impairment of vascular endothelial nitric oxide synthase activity by advanced glycation end products. FASEB J 2003; 17 (10) 1289-1291
    CrossrefPubMedGoogle Scholar
  • 22 Touré F, Fritz G, Li Q. , et al. Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways. Circ Res 2012; 110 (10) 1279-1293
    CrossrefPubMedGoogle Scholar
  • 23 Zhao D, Tong L, Zhang L, Li H, Wan Y, Zhang T. Tanshinone II A stabilizes vulnerable plaques by suppressing RAGE signaling and NF-κB activation in apolipoprotein-E-deficient mice. Mol Med Rep 2016; 14 (06) 4983-4990
    CrossrefPubMedGoogle Scholar
  • 24 Harja E, Bu DX, Hudson BI. , et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice. J Clin Invest 2008; 118 (01) 183-194
    CrossrefPubMedGoogle Scholar
  • 25 Bro S, Flyvbjerg A, Binder CJ. , et al. A neutralizing antibody against receptor for advanced glycation end products (RAGE) reduces atherosclerosis in uremic mice. Atherosclerosis 2008; 201 (02) 274-280
    CrossrefPubMedGoogle Scholar
  • 26 Ikeda K, Higashi T, Sano H. , et al. N (epsilon)-(carboxymethyl)lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction. Biochemistry 1996; 35 (24) 8075-8083
    CrossrefPubMedGoogle Scholar
  • 27 Belmokhtar K, Ortillon J, Jaisson S. , et al. Receptor for advanced glycation end products: a key molecule in the genesis of chronic kidney disease vascular calcification and a potential modulator of sodium phosphate co-transporter PIT-1 expression. Nephrol Dial Transplant 2019; 34 (12) 2018-2030
    CrossrefPubMedGoogle Scholar
  • 28 Adam F, Khatib AM, Lopez JJ. , et al. Apelin: an antithrombotic factor that inhibits platelet function. Blood 2016; 127 (07) 908-920
    CrossrefPubMedGoogle Scholar
  • 29 Gorisse L, Pietrement C, Vuiblet V. , et al. Protein carbamylation is a hallmark of aging. Proc Natl Acad Sci U S A 2016; 113 (05) 1191-1196
    CrossrefPubMedGoogle Scholar
  • 30 Li W, McIntyre TM, Silverstein RL. Ferric chloride-induced murine carotid arterial injury: a model of redox pathology. Redox Biol 2013; 1: 50-55
    CrossrefPubMedGoogle Scholar
  • 31 Semba RD, Fink JC, Sun K, Windham BG, Ferrucci L. Serum carboxymethyl-lysine, a dominant advanced glycation end product, is associated with chronic kidney disease: the Baltimore longitudinal study of aging. J Ren Nutr 2010; 20 (02) 74-81
    CrossrefPubMedGoogle Scholar
  • 32 Foell D, Ichida F, Vogl T. , et al. S100A12 (EN-RAGE) in monitoring Kawasaki disease. Lancet 2003; 361 (9365): 1270-1272
    CrossrefPubMedGoogle Scholar
  • 33 London GM, Drueke TB. Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int 1997; 51 (06) 1678-1695
    CrossrefPubMedGoogle Scholar
  • 34 Jin X, Yao T, Zhou Z. , et al. Advanced glycation end products enhance macrophages polarization into M1 phenotype through activating RAGE/NF-κB pathway. BioMed Res Int 2015; 2015: 732450
    PubMedGoogle Scholar
  • 35 Liabeuf S, Drüeke TB, Massy ZA. Protein-bound uremic toxins: new insight from clinical studies. Toxins (Basel) 2011; 3 (07) 911-919
    CrossrefPubMedGoogle Scholar
  • 36 Gawlowski T, Stratmann B, Ruetter R. , et al. Advanced glycation end products strongly activate platelets. Eur J Nutr 2009; 48 (08) 475-481
    CrossrefPubMedGoogle Scholar
  • 37 Herczenik E, Bouma B, Korporaal SJ. , et al. Activation of human platelets by misfolded proteins. Arterioscler Thromb Vasc Biol 2007; 27 (07) 1657-1665
    CrossrefPubMedGoogle Scholar
  • 38 Zhu W, Li W, Silverstein RL. Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36. Blood 2012; 119 (25) 6136-6144
    CrossrefPubMedGoogle Scholar
  • 39 Ahrens I, Chen YC, Topcic D. , et al. HMGB1 binds to activated platelets via the receptor for advanced glycation end products and is present in platelet rich human coronary artery thrombi. Thromb Haemost 2015; 114 (05) 994-1003
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 40 Bruchfeld A, Qureshi AR, Lindholm B. , et al. High mobility group box protein-1 correlates with renal function in chronic kidney disease (CKD). Mol Med 2008; 14 (3-4): 109-115
    CrossrefPubMedGoogle Scholar
  • 41 Yago T, Liu Z, Ahamed J, McEver RP. Cooperative PSGL-1 and CXCR2 signaling in neutrophils promotes deep vein thrombosis in mice. Blood 2018; 132 (13) 1426-1437
    CrossrefPubMedGoogle Scholar
  • 42 Naganuma T, Tsujita K, Mitomo S. , et al. Impact of chronic kidney disease on outcomes after percutaneous coronary intervention for chronic total occlusions (from the Japanese Multicenter Registry). Am J Cardiol 2018; 121 (12) 1519-1523
    CrossrefPubMedGoogle Scholar
  • 43 Sato T, Hatada K, Kishi S. , et al. Comparison of clinical outcomes of coronary artery stent implantation in patients with end-stage chronic kidney disease including hemodialysis for three everolimus eluting (EES) stent designs: bioresorbable polymer-EES, platinum chromium-EES, and cobalt chrome-EES. J Interv Cardiol 2018; 31 (02) 170-176
    CrossrefPubMedGoogle Scholar
  • 44 Chitalia VC, Shivanna S, Martorell J. , et al. Uremic serum and solutes increase post-vascular interventional thrombotic risk through altered stability of smooth muscle cell tissue factor. Circulation 2013; 127 (03) 365-376
    CrossrefPubMedGoogle Scholar
  • 45 Jain N, Li X, Adams-Huet B. , et al. Differences in whole blood platelet aggregation at baseline and in response to aspirin and aspirin plus clopidogrel in patients with versus without chronic kidney disease. Am J Cardiol 2016; 117 (04) 656-663
    CrossrefPubMedGoogle Scholar