title: Deleterious vascular effects of indoxyl sulfate and reversal by oral adsorbent AST-120.
abstract: BACKGROUND
  In chronic kidney disease (CKD), blood vessels are permanently exposed to uremic toxins such as indoxyl sulfate (IS). We hypothesized that IS could alter vascular tone and that reducing its serum concentration could be beneficial.
  
  
  METHODS
  We studied acute and longer-term effects of IS and AST-120, an oral charcoal adsorbent, on vascular reactivity, endothelium integrity and expression of adhesion molecules VCAM-1 and ICAM-1 in aortic rings of normal and uremic wild type (WT) mice in vitro, and the cardiovascular effects of AST-120 in both WT and apoE-/- mice with CKD in vivo.
  
  
  RESULTS
  In vitro, 1.0 mM IS acutely reduced vascular relaxation (64% for IS 1.0 mM vs. 80% for control, p < 0.05). The effect was more marked after 4 days exposure (39% for IS 1.0 mM 4 days; p < 0.001, prolonged vs. acute exposure), and was associated with endothelial cell loss and upregulation of ICAM-1/VCAM-1 expression. In vitro, AST-120 restored normal vascular function and prevented IS induced endothelial cell loss and ICAM-1/VCAM-1 upregulation. In vivo, AST-120 treatment of CKD mice (1) improved vascular relaxation (72% vs. 48% maximal relaxation in treated vs. untreated mice, p < 0.001), (2) reduced aortic VCAM-1 and ICAM-1 expression, (3) decreased aorta systolic expansion rate (9 ± 3% CKD vs. 14 ± 3% CKD + AST-120, p < 0.02), and (4) prevented the increase in pulse wave velocity (3.56 ± 0.17 m/s CKD vs. 3.10 ± 0.08 m/s CKD + AST-120, p < 0.006). Similar changes were observed in apoE-/- mice.
  
  
  CONCLUSIONS
  IS appears to be an important contributor to the vascular dysfunction associated with CKD. AST-120 treatment ameliorates this dysfunction, possibly via a decrease in serum IS concentration.
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Six
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Gross
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Mathieu C
authors.initials: MC
authors.lastname: Rémond
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Chillon
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Poirot
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France.
authors.forename: Tilman B
authors.initials: TB
authors.lastname: Drueke
authors.affiliation: INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France; Division of Nephrology, Ambroise Paré University Hospital, AP-HP, Paris-Ile-de-France-Ouest University (UVSQ), Boulogne-Billancourt, France. Electronic address: ziad.massy@apr.aphp.fr.
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
mesh_terms: D000284:Administration, Oral; D000327:Adsorption; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D001794:Blood Pressure; D002244:Carbon / Q000008:administration & dosage*; D002318:Cardiovascular Diseases / Q000150:complications / Q000188:drug therapy*; D002470:Cell Survival; D004452:Echocardiography; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007200:Indican / Q000009:adverse effects* / Q000737:chemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010087:Oxides / Q000008:administration & dosage*; D063177:Pulse Wave Analysis; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy*; D014511:Uremia / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C090509:Icam1 protein, mouse; D010087:Oxides; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D002244:Carbon; C040896:AST 120; D007200:Indican
keywords: AST-120; CKD; Endothelial dysfunction; Indoxyl sulfate; Mouse