The RAGE/DIAPH1 Signaling Axis & Implications for the Pathogenesis of Diabetic Complications

Abstract

Increasing evidence links the RAGE (receptor for advanced glycation end products)/DIAPH1 (Diaphanous 1) signaling axis to the pathogenesis of diabetic complications. RAGE is a multi-ligand receptor and through these ligand-receptor interactions, extensive maladaptive effects are exerted on cell types and tissues targeted for dysfunction in hyperglycemia observed in both type 1 and type 2 diabetes. Recent evidence indicates that RAGE ligands, acting as damage-associated molecular patterns molecules, or DAMPs, through RAGE may impact interferon signaling pathways, specifically through upregulation of IRF7 (interferon regulatory factor 7), thereby heralding and evoking pro-inflammatory effects on vulnerable tissues. Although successful targeting of RAGE in the clinical milieu has, to date, not been met with success, recent approaches to target RAGE intracellular signaling may hold promise to fill this critical gap. This review focuses on recent examples of highlights and updates to the pathobiology of RAGE and DIAPH1 in diabetic complications.

Keywords: DIAPH1; RAGE; diabetes; diabetic accelerated atherosclerosis; diabetic complications; diabetic kidney disease; interferon pathway; small molecule antagonist.

Figure 1

Ligand-dependent RAGE oligomerization facilitates binding of the intracellular domain of RAGE to the FH1-FH2 domains of DIAPH1. RAGE homodimers are illustrated in purple and yellow, respectively, and RAGE ligand (S100B) is in pink. Adapted from Reference [11], Xue et al. (Figure 5).

Figure 2

Examples of RAGE-directed therapies. Shown in the Figure (left side) are examples of strategies that target one or more of the RAGE extracellular domains; shown in the Figure (right side) are examples of strategies that target the ligands that may bind to RAGE. At Figure center, bottom, are depicted examples of strategies that target the interaction of the RAGE cytoplasmic domain with DIAPH1.