The Role of AGE-RAGE Signalling as a Modulator of Gut Permeability in Diabetes

Abstract

There is increasing evidence for the role of intestinal permeability as a contributing factor in the pathogenesis of diabetes; however, the molecular mechanisms are poorly understood. Advanced glycation endproducts, of both exogenous and endogenous origin, have been shown to play a role in diabetes pathophysiology, in part by their ligation to the receptor for advanced glycation endproducts (RAGE), leading to a proinflammatory signalling cascade. RAGE signalling has been demonstrated to play a role in the development of intestinal inflammation and permeability in Crohn's disease and ulcerative colitis. In this review, we explore the role of AGE-RAGE signalling and intestinal permeability and explore whether activation of RAGE on the intestinal epithelium may be a downstream event contributing to the pathogenesis of diabetes complications.

Keywords: advanced glycation endproducts; diabetes; intestinal permeability; receptor for advanced glycation endproducts.

Figure 1

Overview of the Maillard reaction generating advanced glycation endproducts (AGEs). In the initial stages, the carbonyl group of a reducing sugar reacts with the amine group from an arginine or lysine residue to form a Schiff base. After a reshuffling process, the Amadori product is formed. Subsequent steps lead to formation of highly reactive α-dicarbonyls that can cross-link with endogenous proteins to form the resulting AGEs. Created with BioRender.com.

Figure 2

The structure of full length and soluble RAGE (Adapted from Lee and Park, 2013). Created with BioRender.com.

Figure 3

The RAGE signalling cascade (adapted from Gugliucci et al., 2014). RAGE is a multiligand receptor of the immunoglobulin gene family. Ligands include free and protein-bound AGEs, DNA, mRNA, High Mobility Group B1 (HMGB1) and S100 proteins. Upon ligation, RAGE can upregulate the overproduction of reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and activate a number of signalling cascades via phosphatidylinositol-3 kinase (PI3K), MAPK (ERK1 and 2), and Ki-Ras pathways to activate nuclear factor-κB (NF-κB). NF-κB can promote the production of ROS, ultimately leading to cellular damage and the dysfunction of mitochondria. NF-κB can also translocate to the nucleus to transcribe a number of pro-inflammatory cytokines and chemokines, including tumour necrosis factor α (TNF α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which promote inflammation and stimulation of immune cells. RAGE expression is also increased. Hyperreactive immune cells can further exacerbate inflammation and ROS production, leading to further complications such as damage to microvasculature in the kidneys and eyes [50]. Created with BioRender.com.

Figure 4

Schematic of tight junction and associated proteins from the intestinal epithelium (adapted from Suzuki, 2020). ZO-1 = Zonula Occludens-1.

Figure 5

Proposed mechanism of RAGE-induced gut barrier dysfunction. Advanced Glycation Endproducts (AGEs) bind to the receptor for advanced glycation endproducts (RAGE) on the cell surface of gut epithelial cells to increase the permeability of the intestinal epithelial barrier. In turn, toxins from bacteria such as lipopolysaccharides (LPS) in the gut lumen are able to cross the barrier into the systemic circulation to trigger an inflammatory response, which may contribute to kidney injury. Created with BioRender.com.