A neutralizing antibody against receptor for advanced glycation end products (RAGE) reduces atherosclerosis in uremic mice.
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.
Bro
Susanne
S
Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. susannebro@dadlnet.dk
Flyvbjerg
Allan
A
Binder
Christoph J
CJ
Bang
Christian A
CA
Denner
Larry
L
Olgaard
Klaus
K
Nielsen
Lars B
LB
D000818:Animals; D000906:Antibodies / Q000378:metabolism*; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D000939:Epitopes / Q000737:chemistry; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014511:Uremia / Q000378:metabolism* / Q000628:therapy; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000906:Antibodies; D000939:Epitopes; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D019010:Vascular Cell Adhesion Molecule-1