Unlocking the biology of RAGE in diabetic microvascular complications

Abstract

The discovery of the receptor for advanced glycation end-products (RAGE) set the stage for the elucidation of important mechanisms underpinning diabetic complications. RAGE transduces the signals of advanced glycation end-products (AGEs), proinflammatory S100/calgranulins, and high mobility group box 1 (HMGB1), and is a one of a family of receptors for lysophosphatidic acid (LPA). These ligand tales weave a theme of vascular perturbation and inflammation linked to the pathogenesis of the chronic complications of diabetes. Once deemed implausible, this concept of inflammatory cues participating in diabetic complications is now supported by a plethora of experimental evidence in the macro- and microvasculature. We review the biology of ligand-RAGE signal transduction and its roles in diabetic microvascular complications, from animal models to human subjects.

Keywords: complications; diabetes; inflammation; ligands; receptor for AGE.

Figure 1. The ligands of 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 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, upregualtion 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 infalmmatory response by (1) increasing vascular permeability and endothelial dysfunction; and (2) polarizing macrophages to a predominant “M1” vs. “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 complciations of diabetes.