title: Prevention of accelerated atherosclerosis by AT1 receptor blockade in experimental renal failure.
abstract: BACKGROUND
  The mechanisms of uraemia-induced atherosclerosis have not been fully delineated. The aims of this study were (i) to investigate the extent and the phenotype of atherosclerosis, including the activation of local renin-angiotensin system (RAS), in a mouse model of mild uraemia and (ii) to determine the effects of angiotensin II type1 (AT1) receptor blockade on the uraemic atherosclerosis, clarifying the mechanisms of its action.
  
  
  METHODS
  Mild uraemia was induced by 5/6 nephrectomy in 8-week-old apo E-deficient mice (apoE-KO). After nephrectomy, the animals received either treatment with candesartan or no treatment for 12-weeks. Sham-operated apoE-KO mice were used as controls.
  
  
  RESULTS
  Uraemia led to a two-fold increase in aortic plaque area. This was associated with a significant upregulation of aortic angiotensin-converting enzyme (ACE), AT1 receptor, connective tissue growth factor (CTGF), monocyte chemoattractant protein (MCP)-1 and vascular cell adhesion molecule (VCAM)-1. Candesartan significantly reduced aortic atherosclerosis, prevented the upregulation of the uraemia-induced genes and led to changes predicting greater stability of the plaques, without influencing blood pressure or serum lipids.
  
  
  CONCLUSIONS
  This study indicates that uraemia leads to an acceleration of aortic atherosclerosis. The upregulation of aortic RAS and the reduced atherosclerosis following AT1 receptor blocker treatment highlights the pivotal role of the local RAS in the development and acceleration of atherosclerosis in uraemia.
authors.affiliation: DUCSMTT, University of Trieste, Trieste, Italy.
authors.forename: Stella
authors.initials: S
authors.lastname: Bernardi
authors.forename: Riccardo
authors.initials: R
authors.lastname: Candido
authors.forename: Barbara
authors.initials: B
authors.lastname: Toffoli
authors.forename: Renzo
authors.initials: R
authors.lastname: Carretta
authors.forename: Bruno
authors.initials: B
authors.lastname: Fabris
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000378:metabolism / Q000517:prevention & control*; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009392:Nephrectomy; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000627:therapeutic use; D014511:Uremia / Q000378:metabolism / Q000517:prevention & control
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; C081643:candesartan