Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:905-910
© 2001 American Heart Association, Inc.
Vascular Biology |
Receptor for Advanced Glycation End Products Mediates Inflammation and Enhanced Expression of Tissue Factor in Vasculature of Diabetic Apolipoprotein E–Null Mice
From the College of Physicians and Surgeons, Columbia University, New York, New York, and Institut für Pharmazie und Lebensmittelchemie (M.P.), Abteilung Lebensmittelchemie, Universität Erlangen-Nürnberg, Erlangen, Germany.
Correspondence to Dr Ann Marie Schmidt, College of Physicians and Surgeons, Columbia University, 630 West 168th St, P&S 17-501, New York, NY 10032. E-mail ams11{at}columbia.edu
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-ß, fibronectin, and
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.
Key Words: receptor for advanced glycation end products • glycation • diabetes • nephropathy • atherosclerosis
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