Receptor for advanced glycation end products mediates inflammation and enhanced expression of tissue factor in vasculature of diabetic apolipoproteinE-null mice

Advanced glycation end products (AGEs) and their cell surface receptor, RAG E, 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 a ctivation in diabetic tissue. Apolipoprotein E-null mice were rendered diab etic with streptozotocin at 6 weeks of age. Compared with nondiabetic aorta s and kidneys, diabetic aortas and kidneys displayed increased expression o f RAGE, EN-RAGEs, and 2 key markers of vascular inflammation, vascular cell adhesion molecule (VCAM)-1 and tissue factor. Administration of soluble RA GE, the extracellular domain of the receptor, or vehicle to diabetic mice f or 6 weeks suppressed levels of VCAM-1 and tissue factor in the aorta, in p arallel with decreased expression of RAGE and EN-RAGEs. Diabetic kidney dem onstrated increased numbers of EN-RAGE-expressing inflammatory cells infilt rating the glomerulus and enhanced mRNA for transforming growth factor-beta , fibronectin, and alpha (1) (IV) collagen. In mice treated with soluble RA GE, the numbers of infiltrating inflammatory cells and mRNA levels for thes e glomerular cytokines and components of extracellular matrix were decrease d. These data suggest that activation of RAGE primes cells targeted for per turbation in diabetic tissues by the induction of proinflammatory mediators .