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A neutralizing antibody against receptor for advanced glycation end products (RAGE) reduces atherosclerosis in uremic
Susanne Bro1, Allan Flyvbjerg, Christoph J Binder
1Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. susannebro@dadlnet.dk
Abstract:
Chronic renal failure markedly accelerates atherogenesis in apolipoprotein E-deficient (apoE(-/-)) mice. To study the putative role of receptor for advanced glycation end products (RAGE) in development of uremic atherosclerosis, apoE(-/-) mice received intraperitoneal injections thrice weekly of a neutralizing murine RAGE-antibody (RAGE-ab) (n=21) or an isotype-matched control antibody (placebo-ab) (n=23). Treatment was started 4 weeks after surgical 5/6 nephrectomy in 16 weeks old mice and continued for 12 weeks. The RAGE-ab did not affect blood pressure, plasma cholesterol or measures of uremia. However, the aortic plaque area fraction was reduced by 59% in RAGE-ab compared with placebo-ab-treated mice (0.016 +/- 0.002 versus 0.039 +/- 0.005, P<0.001). In plasma, the RAGE-ab reduced concentrations of oxidized phospholipid neo-epitopes in plasma as detected by the specific monoclonal antibody EO6 (P<0.05) and titers of IgG antibodies against oxidized low-density lipoprotein (P<0.001). In the aorta of treated mice, the RAGE-ab did not affect the mRNA expression of eight selected genes associated with inflammation. The results suggest that blockade of RAGE reduces the proatherogenic effects of uremia, possibly through a systemic decrease in oxidative stress.
Insights
Blocking the receptor for advanced glycation end products (RAGE) significantly reduced atherosclerosis in mice with chronic kidney disease. This suggests RAGE blockade may combat uremic atherosclerosis by decreasing oxidative stress.
Area of Science:
- Nephrology
- Cardiovascular Research
- Immunology
Background:
- Chronic kidney disease accelerates atherosclerosis.
- The receptor for advanced glycation end products (RAGE) is implicated in uremic atherosclerosis.
- Apolipoprotein E-deficient (apoE(-/-)) mice are a model for studying atherosclerosis.
Purpose of the Study:
- To investigate the role of RAGE in the development of atherosclerosis in chronic renal failure.
- To determine if neutralizing RAGE with an antibody affects uremic atherosclerosis progression.
Main Methods:
- Apolipoprotein E-deficient (apoE(-/-)) mice underwent 5/6 nephrectomy to induce chronic renal failure.
- Mice were treated with a neutralizing RAGE-antibody or a control antibody for 12 weeks.
- Aortic plaque area, plasma biomarkers, and aortic gene expression were analyzed.
Main Results:
- RAGE-antibody treatment significantly reduced aortic plaque area by 59% compared to controls (P<0.001).
- RAGE-antibody treatment decreased plasma concentrations of oxidized phospholipid neo-epitopes and antibodies against oxidized LDL.
- Blood pressure, plasma cholesterol, and uremia markers were unaffected by RAGE-antibody treatment.
Conclusions:
- Blockade of RAGE effectively reduces the proatherogenic effects of uremia in apoE(-/-) mice.
- RAGE inhibition may mitigate uremic atherosclerosis, potentially via a systemic reduction in oxidative stress.
- Targeting RAGE represents a potential therapeutic strategy for managing atherosclerosis in chronic kidney disease patients.
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