Background-Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice. Methods and Results-Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed. Conclusions-RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.

Receptor for advanced glycation end-products (RAGE), and two of its ligands, AGE and EN-RAGEs (members of the S100/calgranulin family of pro-inflammatory cytokines), display enhanced expression in slowly resolving full-thickness excisional wounds developed in genetically diabetic db+/db+ mice. We tested the concept that blockade of RAGE, using soluble(s) RAGE, the extracellular ligand-binding domain of the receptor, would enhance wound closure in these animals. Administration of sRAGE accelerated the development of appropriately limited inflammatory cell infiltration and activation in wound foci. In parallel with accelerated wound closure at later times, blockade of RAGE suppressed levels of cytokines; tumor necrosis factor-alpha; interleukin-6; and matrix metalloproteinases-2, -3, and -9. In addition, generation of thick, well-vascularized granulation tissue was enhanced, in parallel with increased levels of platelet-derived growth factor-B and vascular endothelial growth factor. These findings identify a central role for RAGE in disordered wound healing associated with diabetes, and suggest that blockade of this receptor might represent a targeted strategy to restore effective wound repair in this disorder.

Receptor for AGE (RAGE) is a member of the immunoglobulin superfamily that engages distinct classes of ligands. The biology of RAGE is driven by the settings in which these ligands accumulate, such as diabetes, inflammation, neurodegenerative disorders and tumors. In this review, we discuss the context of each of these classes of ligands, including advance glycation end-products, amyloid beta peptide and the family of beta sheet fibrils, S100/calgranulins and amphoterin. Implications for the role of these ligands interacting with RAGE in homeostasis and disease will be considered.

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-␤, 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.

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