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Updated: Jun 9, 2026
A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis
Published on: October 26, 2020
Prevention of accelerated atherosclerosis by AT1 receptor blockade in experimental renal failure
Stella Bernardi1, Riccardo Candido, Barbara Toffoli
1DUCSMTT, University of Trieste, Trieste, Italy.
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.
Insights
Uremia accelerates atherosclerosis by activating the local renin-angiotensin system (RAS). Blocking the angiotensin II type 1 (AT1) receptor with candesartan reduced this uraemic atherosclerosis without affecting blood pressure or lipids.
Area of Science:
- Cardiovascular Research
- Nephrology
- Atherosclerosis Research
Background:
- Mechanisms of uremia-induced atherosclerosis remain unclear.
- Uremia is associated with accelerated cardiovascular disease.
- Local renin-angiotensin system (RAS) activation is implicated in atherosclerosis.
Purpose of the Study:
- Investigate atherosclerosis extent and phenotype in a mild uremia mouse model.
- Examine local RAS activation in uremic atherosclerosis.
- Determine the effect of angiotensin II type 1 (AT1) receptor blockade on uremic atherosclerosis.
Main Methods:
- Mild uremia induced via 5/6 nephrectomy in apoE-deficient mice (apoE-KO).
- Mice treated with candesartan (AT1 receptor blocker) or no treatment for 12 weeks.
- Sham-operated apoE-KO mice served as controls.
Main Results:
- Uremia doubled aortic plaque area, upregulating ACE, AT1 receptor, CTGF, MCP-1, and VCAM-1.
- Candesartan significantly reduced aortic atherosclerosis and prevented gene upregulation.
- AT1 receptor blockade improved plaque stability without altering blood pressure or serum lipids.
Conclusions:
- Uremia accelerates aortic atherosclerosis.
- Upregulation of the local RAS plays a pivotal role in uremic atherosclerosis development.
- AT1 receptor blockade effectively reduces uremic atherosclerosis, highlighting the RAS as a therapeutic target.
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