Vascular Remodeling and Arterial Calcification Are Directly Mediated by S100A12 (EN-RAGE) in Chronic Kidney Disease

Background: The proinflammatory cytokine S100A12 (also known as EN-RAGE) is associated with cardiovascular morbidity and mortality in hemodialysis patients. In the current study, we tested the hypothesis that S100A12 expressed in vascular smooth muscle in nonatherosclerosis-prone C57BL/6J mice on normal rodent chow diet, but exposed to the metabolic changes of chronic kidney disease (CKD), would develop vascular disease resembling that observed in patients with CKD. Methods: CKD was induced in S100A12 transgenic mice and wild-type littermate mice not expressing human S100A12 by surgical ligation of the ureters. The aorta was analyzed after 7 weeks of elevated BUN (blood urea nitrogen), and cultured aortic smooth muscle cells were studied. Results: We found enhanced vascular medial calcification in S100A12tg mice subjected to CKD. Vascular calcification was mediated, at least in part, by activation of the receptor for S100A12, RAGE (receptor for advanced glycation endproducts), and by enhanced oxidative stress, since inhibition of NADPH-oxidase Nox1 and limited access of S100A12 Received: January 11, 2011 Accepted: January 27, 2011 Published online: March 2, 2011 Nephrology American Journal of Marion A. Hofmann Bowman Section of Cardiology, Department of Medicine University of Chicago 5841 S. Maryland Avenue MC 6088, Chicago, IL 60637 (USA) Tel. +1 773 834 0807, E-Mail mhofmann @ medicine.bsd.uchicago.edu © 2011 S. Karger AG, Basel Accessible online at: www.karger.com/ajn D ow nl oa de d by : 54 .1 91 .4 0. 80 5 /2 /2 01 7 11 :5 0: 13 A M