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 It, 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. (C) 2008 Elsevier Ireland Ltd. All rights reserved.