Receptor for Advanced Glycation End Products Mediates Inflammation and Enhanced Expression of Tissue Factor in Vasculature of Diabetic Apolipoprotein E–Null Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 21; no. 6; pp. 905 - 910
• Main Authors: Kislinger, Thomas, Tanji, Nozomu, Wendt, Thoralf, Qu, Wu, Lu, Yan, Ferran, Luis J, Taguchi, Akihiko, Olson, Kim, Bucciarelli, Loredana, Goova, Mouza, Hofmann, Marion A, Cataldegirmen, Guellue, D’Agati, Vivette, Pischetsrieder, Monika, Stern, David M, Schmidt, Ann Marie
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-06-2001; Hagerstown, MD Lippincott
• Subjects: Animals; Aorta - metabolism; Apolipoproteins E - genetics; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diabetes Mellitus, Experimental - complications; Kidney - metabolism; Leukocyte L1 Antigen Complex; Male; Medical sciences; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Cell Adhesion Molecules - metabolism; NF-kappa B - metabolism; Receptor for Advanced Glycation End Products; Receptors, Immunologic - physiology; Thromboplastin - biosynthesis; Vascular Cell Adhesion Molecule-1 - metabolism; Vasculitis - complications; Vasculitis - metabolism; Endocrinopathy; Kidney disease; Urinary system disease; Pathogenesis; Diabetes mellitus; Rodentia; Tissue factor; Cardiovascular disease; Inflammation; Glycation; Vascular disease; Vertebrata; Mammalia; Nephropathy; Mouse; Animal; Blood vessel; Atherosclerosis; Risk factor
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.atv.21.6.905

ABSTRACT—Advanced glycation end products (AGEs) and their cell surface receptor, RAGE, have been implicated in the pathogenesis of diabetic complications. Here, we studied the role of RAGE and expression of its proinflammatory ligands, EN-RAGEs (S100/calgranulins), in inflammatory events mediating cellular activation in diabetic tissue. Apolipoprotein E– null mice were rendered diabetic with streptozotocin at 6 weeks of age. Compared with nondiabetic aortas and kidneys, diabetic aortas and kidneys displayed increased expression of RAGE, EN-RAGEs, and 2 key markers of vascular inflammation, vascular cell adhesion molecule (VCAM)-1 and tissue factor. Administration of soluble RAGE, the extracellular domain of the receptor, or vehicle to diabetic mice for 6 weeks suppressed levels of VCAM-1 and tissue factor in the aorta, in parallel with decreased expression of RAGE and EN-RAGEs. Diabetic kidney demonstrated increased numbers of EN-RAGE–expressing inflammatory cells infiltrating the glomerulus and enhanced mRNA for transforming growth factor-β, fibronectin, and α 1 (IV) collagen. In mice treated with soluble RAGE, the numbers of infiltrating inflammatory cells and mRNA levels for these glomerular cytokines and components of extracellular matrix were decreased. These data suggest that activation of RAGE primes cells targeted for perturbation in diabetic tissues by the induction of proinflammatory mediators.