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

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2011-03, Vol.26 (3), p.832-838
• Main Authors: BERNARDI, Stella, CANDIDO, Riccardo, TOFFOLI, Barbara, CARRETTA, Renzo, FABRIS, Bruno
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Animals; Aorta - drug effects; Aorta - pathology; Apolipoproteins E - physiology; Atherosclerosis - metabolism; Atherosclerosis - prevention & control; Benzimidazoles - therapeutic use; Biological and medical sciences; Emergency and intensive care: renal failure. Dialysis management; Intensive care medicine; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephrectomy; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Phenotype; Receptor, Angiotensin, Type 1 - chemistry; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Angiotensin, Type 2 - chemistry; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Renal failure; Renal Insufficiency - drug therapy; Renal Insufficiency - etiology; Renal Insufficiency - metabolism; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Tetrazoles - therapeutic use; Uremia - metabolism; Uremia - prevention & control
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfq524

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. 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. 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. 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.