RAGE signaling regulates the progression of diabetic complications

Abstract

Diabetes, the ninth leading cause of death globally, is expected to affect 642 million people by 2040. With the advancement of an aging society, the number of patients with diabetes having multiple underlying diseases, such as hypertension, obesity, and chronic inflammation, is increasing. Thus, the concept of diabetic kidney disease (DKD) has been accepted worldwide, and comprehensive treatment of patients with diabetes is required. Receptor for advanced glycation endproducts (RAGE), a multiligand receptor, belonging to the immunoglobulin superfamily is extensively expressed throughout the body. Various types of ligands, including advanced glycation endproducts (AGEs), high mobility group box 1, S100/calgranulins, and nucleic acids, bind to RAGE, and then induces signal transduction to amplify the inflammatory response and promote migration, invasion, and proliferation of cells. Furthermore, the expression level of RAGE is upregulated in patients with diabetes, hypertension, obesity, and chronic inflammation, suggesting that activation of RAGE is a common denominator in the context of DKD. Considering that ligand-and RAGE-targeting compounds have been developed, RAGE and its ligands can be potent therapeutic targets for inhibiting the progression of DKD and its complications. Here, we aimed to review recent literature on various signaling pathways mediated by RAGE in the pathogenesis of diabetic complications. Our findings highlight the possibility of using RAGE-or ligand-targeted therapy for treating DKD and its complications.

Keywords: AGEs; DNA aptamer; chronic kidney disease; diabetic nephropathy; receptor for advanced glycation endproducts.

FIGURE 1

Intracellular RAGE signaling. The engagement of RAGE with several ligands including AGEs, HMGB-1, S100/calcinurins is involved in profibrotic and inflammatory response, cell adhesion, angiogenesis, and thrombogenesis.

FIGURE 2

RAGE and other signaling are implicated in EndMT in diabetes. EndMT contributes to tissue fibrosis in diabetic condition. The engagement of RAGE with AGEs induces EndMT through the activation of Smad2/3 or aberrant upregulation of autophagy. TGF-β also activates Smad2/3, leading to EndMT. RAGE-induced increase in TGF-β amplifies EndMT, resulting in tissue fibrosis. Besides, Notch signaling or Wnt/β-catenin pathway is involved in EndMT as well. EndMT, endothelial-to-mesenchymal transition; TGF-β, tissue growth factor-b; RAGE, receptor for advanced glycation endproducts; VE-cadherin, vascular endothelial-cadherin; vWF, von Willebrand factor; α-SMA, a-smooth muscle actin; FSP, fibroblast-specific protein; sm22-α, smooth muscle protein 22.

FIGURE 3

The interaction between RAGE and MR in podocytes. Aldosterone produces ONOO⁻ through the interaction with MR, which, in turn, promotes intracellular Nε-CML production in podocytes. RAGE is activated by the Nε-CML in an autocrine manner and the RAGE activation upregulates MR expression that forms a vicious cycle to induce podocytopathy. The vicious cycle is blocked by the inhibition of RAGE, leading to attenuate podocyte injury. RAGE, receptor for advanced glycation endproducts; MR, mineralocorticoid receptor.