Figure 1: The relationship between binding of ligands to the pattern recognition AGE receptor, RAGE and inflammation, gene expression, oxidative and nitrosative stress, and damage to the macro- and microvasculature. Elevated levels of glucose bind to proteins and form AGEs (I), which bind to RAGEs. RAGE signaling activates NADPH oxidase (II) and production of reactive oxygen species (ROS) (III). Increased ROS increases advance oxidation protein products (AOPPs), more AGEs, and AGE-modification of oxidized LDLs (oxLDLs). Furthermore, increased ROS may deplete glutathione, thereby suppressing glyoxalase I activity, a mechanism favoring further AGE accumulation (IV). AGEs, AOPPs, macrophage glycoprotein (MAC-1), and AGE-oxLDL ligands of RAGE sustain stimulation of RAGE, and these processes, together with increased ROS, activate key transcription factors such as nuclear factor-κB (NF-κB) and Egr-1 (V), which increase gene transcription factors and activate inflammatory mechanisms (VI). Consequences include increased migration and activation of RAGE-expressing neutrophils, monocytes/macrophages, T-cells, and dendritic cells (VII). This results in the release of the proinflammatory RAGE ligands S100/calgranulins and high-mobility group protein box-1 (HMGB1). In this inflammatory environment, further AGEs may be formed as well. Via interaction with RAGE, these ligands magnify activation of NF-κB, Agr-1, and other factors (VIII), thereby amplifying cellular stress and tissue damage leading to neurovascular and bone dysfunction. Soluble RAGE (sRAGE) formed from cleavage of RAGE by disintegrins such as ADAM 10, a metalloproteinase, and β- and γ-secretases. sRAGE or a spliced variant (esRAGE) compete for binding of ligands to RAGE, and a deficiency could theoretically initiate the sequence of events activating an inflammatory cascade with an increase in the expression of proinflammatory cytokines (E-selectin, endothelin-1 tissue factor, vascular endothelial growth factor, and other proinflammatorycytokines [interleukin-6 and tumor necrosis factor-α]) and damage to neurons, kidney, eye, the vasculature, and even bone. Increasing sRAGE or its administration could competitively reduce activation of the AGE/RAGE pathway and it consequences, reproduced with permission from [42].