Unlocking the biology of RAGE in diabetic microvascular complications Michaele B. Manigrasso, Judyta Juranek, Ravichandran Ramasamy, Ann Marie Schmidt  Trends in Endocrinology & Metabolism  Volume 25, Issue 1, Pages 15-22 (January 2014) DOI: 10.1016/j.tem.2013.08.002 Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 1 The ligands of the receptor for advanced glycation end-products (RAGE) and the complications of diabetes – one ligand at a time? We hypothesize that the key trigger to activation of RAGE in diabetes is hyperglycemia-mediated generation of advanced glycation end-products (AGEs). When AGEs interact with RAGE, they stimulate generation of reactive oxygen species (ROS); ROS contribute to further generation of AGEs. Once AGE–RAGE interaction is set in motion, upregulation of inflammatory cell adhesion molecules and chemokines results; the recruitment of inflammatory cells to the vessel wall results in inflammatory cell activation and release of RAGE ligands, S100/calgranulins and HMGB1. These molecules sustain the inflammatory response by (i) increasing vascular permeability and endothelial dysfunction, and (ii) polarizing macrophages to a predominant ‘M1’ versus ‘M2’ paradigm. Such a shift increases inflammatory/tissue-damaging signals (M1) and suppresses repair/remodeling (M2) signatures. Together, these forces converge to contribute to the macro- and microvascular complications of diabetes. Trends in Endocrinology & Metabolism 2014 25, 15-22DOI: (10.1016/j.tem.2013.08.002) Copyright © 2013 Elsevier Ltd Terms and Conditions