Dual Nature of RAGE in Host Reaction and Nurturing the Mother–Infant Bond

Abstract

Non-enzymatic glycation is an unavoidable reaction that occurs across biological taxa. The final products of this irreversible reaction are called advanced glycation end-products (AGEs). The endogenously formed AGEs are known to be bioactive and detrimental to human health. Additionally, exogenous food-derived AGEs are debated to contribute to the development of aging and various diseases. Receptor for AGEs (RAGE) is widely known to elicit biological reactions. The binding of RAGE to other ligands (e.g., high mobility group box 1, S100 proteins, lipopolysaccharides, and amyloid-β) can result in pathological processes via the activation of intracellular RAGE signaling pathways, including inflammation, diabetes, aging, cancer growth, and metastasis. RAGE is now recognized as a pattern-recognition receptor. All mammals have RAGE homologs; however, other vertebrates, such as birds, amphibians, fish, and reptiles, do not have RAGE at the genomic level. This evidence from an evolutionary perspective allows us to understand why mammals require RAGE. In this review, we provide an overview of the scientific knowledge about the role of RAGE in physiological and pathological processes. In particular, we focus on (1) RAGE biology, (2) the role of RAGE in physiological and pathophysiological processes, (3) RAGE isoforms, including full-length membrane-bound RAGE (mRAGE), and the soluble forms of RAGE (sRAGE), which comprise endogenous secretory RAGE (esRAGE) and an ectodomain-shed form of RAGE, and (4) oxytocin transporters in the brain and intestine, which are important for maternal bonding and social behaviors.

Human intestine and placenta exhibit tissue-specific expression of RAGE isoforms

“…Strong evidence implicates RAGE in the pathophysiology of lung diseases [ 62 ] or diabetic complications [ 63 ]. In contrast, information on key aspects of this important innate immune receptor remains sparse in the placenta and intestine, where an involvement of RAGE in the pathogenesis of pregnancy-associated diseases (PE, GDM, FGR) [ 39 , 41 , 43 , [64] , [65] , [66] ] and inflammatory bowel disease [ [30] , [31] , [32] , [67] , [68] , [69] ] has been suspected but remains controversial.…”

An Introduction to the Special Issue “Protein Glycation in Food, Nutrition, Health and Disease”

“…In the Special Issue, there are contributions on the hexokinase-2-linked glycolytic overload initiation of processes leading to dicarbonyl stress in vascular cells in hyperglycemia [ 44 ], the physiological consequences of dicarbonyl stress [ 45 ], the involvement of the receptor for advanced glycation adducts (RAGE) [ 46 ], including the role of AGE-RAGE signalling as a modulator of gut permeability in diabetes [ 47 ], and the emergence of Glo1 inducer therapeutics for the prevention of type 2 diabetes and treatment of vascular complications of diabetes [ 28 ]. The remarkable emerging role of RAGE in early life nurturing as well as the mother–infant bond and the role of glycation in organelle stress as well as metabolic derangement in kidney disease are also described [ 48 , 49 ]. The clinical diagnostics of glycation is now advancing from the role of A1C and glycated albumin in the assessment of glycemic control in diabetes [ 4 ] to the application of machine learning for the development of diagnostic algorithms with combinations of plasma and urinary AGEs as features for the risk prediction of diabetic kidney disease and other clinical conditions [ 50 ].…”