Prevention of accelerated atherosclerosis by AT1 receptor blockade in experimental renal failure

被引:9
作者
Bernardi, Stella [1 ]
Candido, Riccardo [2 ]
Toffoli, Barbara [1 ]
Carretta, Renzo [1 ]
Fabris, Bruno [1 ]
机构
[1] Univ Trieste, DUCSMTT, Trieste, Italy
[2] UO Ctr Diabetol Distretto 3, Trieste, Italy
关键词
angiotensin; AT1 receptor blockers; atherosclerosis; uraemia; ANGIOTENSIN-CONVERTING ENZYME; CHRONIC KIDNEY-DISEASE; ENDOTHELIAL RECEPTOR; BLOOD-PRESSURE; ATHEROGENESIS; INHIBITION; LOSARTAN; EXPRESSION; SYSTEM; UREMIA;
D O I
10.1093/ndt/gfq524
中图分类号
R3 [基础医学]; R4 [临床医学];
学科分类号
1001 ; 1002 ; 100602 ;
摘要
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.
引用
收藏
页码:832 / 838
页数:8
相关论文
共 26 条
[1]   Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice [J].
Bro, S ;
Bentzon, JF ;
Falk, E ;
Andersen, CB ;
Olgaard, K ;
Nielsen, LB .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (10) :2466-2474
[2]   Inhibition of the renin-angiotensin system abolishes the proatherogenic effect of uremia in apolipoprotein E-deficient mice [J].
Bro, Susanne ;
Binder, Christoph J. ;
Witztum, Joseph L. ;
Olgaard, Klaus ;
Nielsen, Lars B. .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2007, 27 (05) :1080-1086
[3]   The apolipoprotein E knockout mouse:: A model documenting accelerated atherogenesis in uremia [J].
Buzello, M ;
Törnig, J ;
Faulhaber, J ;
Ehmke, H ;
Ritz, E ;
Amann, K .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (02) :311-316
[4]   Irbesartan but not amlodipine suppresses diabetes-associated atherosclerosis [J].
Candido, R ;
Allen, TJ ;
Lassila, M ;
Cao, ZM ;
Thallas, V ;
Cooper, ME ;
Jandeleit-Dahm, KA .
CIRCULATION, 2004, 109 (12) :1536-1542
[5]   Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice [J].
Candido, R ;
Jandeleit-Dahm, KA ;
Cao, ZM ;
Nesteroff, SP ;
Burns, WC ;
Twigg, SM ;
Dilley, RJ ;
Cooper, ME ;
Allen, TJ .
CIRCULATION, 2002, 106 (02) :246-253
[6]   ACE inhibitors and survival of hemodialysis patients [J].
Efrati, S ;
Zaidenstein, R ;
Dishy, V ;
Beberashvili, I ;
Sharist, M ;
Averbukh, Z ;
Golik, A ;
Weissgarten, J .
AMERICAN JOURNAL OF KIDNEY DISEASES, 2002, 40 (05) :1023-1029
[7]   Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States medicare population, 1998 to 1999 [J].
Foley, RN ;
Murray, AM ;
Li, SL ;
Herzog, CA ;
McBean, AM ;
Eggers, PW ;
Collins, AJ .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2005, 16 (02) :489-495
[8]   Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization [J].
Go, AS ;
Chertow, GM ;
Fan, DJ ;
McCulloch, CE ;
Hsu, CY .
NEW ENGLAND JOURNAL OF MEDICINE, 2004, 351 (13) :1296-1305
[9]  
GUERIN AP, 1997, HYPERTENSION, V103, P987
[10]   The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice [J].
Hayek, T ;
Attias, J ;
Coleman, R ;
Brodsky, S ;
Smith, J ;
Breslow, JL ;
Keidar, S .
CARDIOVASCULAR RESEARCH, 1999, 44 (03) :579-587