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

Abstract

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.

Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation

“…Diabetic mice demonstrated an upregulation of AGER, as has been shown previously [41]. We have demonstrated a novel finding, that gemfibrozil treatment was associated with an attenuation of Ager expression in diabetic mice.…”

Irbesartan but Not Amlodipine Suppresses Diabetes-Associated Atherosclerosis

“…This chemokine has been reported to play an important role in the development of atherosclerosis in the apoE-null mouse in the absence 24 or presence of diabetes. 25 The endothelial adhesion molecule VCAM-1, which is important for the adhesion of macrophages to the vascular wall, 26,27 was also significantly increased in diabetes and was attenuated by irbesartan. Amlodipine did not have an effect on macrophage or vascular smooth muscle cell infiltration and proliferation or on VCAM-1 and MCP-1 expression, consistent with the failure of this agent to reduce atherosclerosis in this model.…”

AGE/RAGE as a Mediator of Insulin Resistance or Metabolic Syndrome: Another Aspect of Metabolic Memory?

“…Blockade of RAGE by administration of genetically engineered sRAGE successfully prevented the development of micro- 132,133 and macrovascular complications in diabetes [134][135][136] . We have also shown that adenoviral overexpression of esRAGE successfully restored the impaired angiogenic response in diabetic mice 101 .…”