title: Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis.
abstract: Cardiovascular disease is the leading cause of death in patients with end-stage renal disease. Serum amyloid A (SAA) is an acute phase protein and a binding partner for the multiligand receptor for advanced glycation end products (RAGE). We investigated the role of the interaction between SAA and RAGE in uremia-related atherogenesis.
  
  
  
  We used a mouse model of uremic vasculopathy, induced by 5 of 6 nephrectomy in the Apoe(-/-) background. Sham-operated mice were used as controls. Primary cultures of Ager(+/+) and Ager(-/-) vascular smooth muscle cells (VSMCs) were stimulated with recombinant SAA, S100B, or vehicle alone. Relevance to human disease was assessed with human VSMCs. The surface area of atherosclerotic lesions at the aortic roots was larger in uremic Apoe(-/-) than in sham-operated Apoe(-/-) mice (P<0.001). Furthermore, atherosclerotic lesions displayed intense immunostaining for RAGE and SAA, with a pattern similar to that of α-SMA. Ager transcript levels in the aorta were 6× higher in uremic animals than in controls (P<0.0001). Serum SAA concentrations were higher in uremic mice, not only after 4 weeks of uremia but also at 8 and 12 weeks of uremia, than in sham-operated animals. We investigated the functional role of RAGE in uremia-induced atherosclerosis further, in animals lacking RAGE. We found that the induction of uremia in Apoe(-/-) Ager(-/-) mice did not accelerate atherosclerosis. In vitro, the stimulation of Ager(+/+) but not of Ager(-/-) VSMCs with SAA or S100B significantly induced the production of reactive oxygen species, the phosphorylation of AKT and mitogen-activated protein kinase-extracellular signal-regulated kinases and cell migration. Reactive oxygen species inhibition with N-acetyl cysteine significantly inhibited both the phosphorylation of AKT and the migration of VSMCs. Similar results were obtained for human VSMCs, except that the phosphorylation of mitogen-activated protein kinase-extracellular signal-regulated kinases, rather than of AKT, was subject to specific redox-regulation by SAA and S100B. Furthermore, human aortic atherosclerotic sections were positively stained for RAGE and SAA.
  
  
  
  Uremia upregulates SAA and RAGE expression in the aortic wall and in atherosclerotic lesions in mice. Ager(-/-) animals are protected against the uremia-induced acceleration of atherosclerosis. SAA modulates the functions of murine and human VSMCs in vitro in a RAGE-dependent manner. This study, therefore, identifies SAA as a potential new uremic toxin involved in uremia-related atherosclerosis through interaction with RAGE.
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Karim
authors.initials: K
authors.lastname: Belmokhtar
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Robert
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Jeremy
authors.initials: J
authors.lastname: Ortillon
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Antoine
authors.initials: A
authors.lastname: Braconnier
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Vuiblet
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Camille
authors.initials: C
authors.lastname: Boulagnon-Rombi
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Marie Danièle
authors.initials: MD
authors.lastname: Diebold
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Christine
authors.initials: C
authors.lastname: Pietrement
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Rieu
authors.affiliation: From the UFR Medecine, Laboratoire de néphrologie, Faculté de Médecine, Université de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France (K.B., T.R., J.O., V.V., M.D.D., C.P., P.R., F.T.); Division of Nephrology (T.R., A.B., V.V., P.R., F.T.), Division of Anatomopathology (C.B.-R., M.D.D.), and Division of Pediatrics (C.P.), CHU Reims, Reims, France; and Diabetes Research Program, New York University, New York (A.M.S.). ftoure@chu-reims.fr.
authors.forename: Fatouma
authors.initials: F
authors.lastname: Touré
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009392:Nephrectomy; D018384:Oxidative Stress; D010641:Phenotype; D010766:Phosphorylation; D058226:Plaque, Atherosclerotic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism*; D015398:Signal Transduction; D014511:Uremia / Q000150:complications* / Q000235:genetics / Q000378:metabolism
chemical_list: C000593871:AGER protein, human; C000593873:Ager protein, mouse; D000975:Antioxidants; D001057:Apolipoproteins E; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D000685:Serum Amyloid A Protein; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: cardiovascular diseases; mice; nephrectomy; receptor for advanced glycation end products (RAGE); serum amyloid a protein