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.

Advances in understanding and treating diabetic kidney disease: focus on tubulointerstitial inflammation mechanisms

“…AGEs are formed through non-enzymatic reactions between reducing sugars and proteins, amino acids, and other molecules ( 66 ).. Notably, the proximal tubule serves as the principal site for AGE reabsorption ( 67 ).…”

“…In the context of diabetes, the number of binding sites for AGEs on the proximal renal tubules increases ( 66 ). Upon binding to their receptors, AGEs can induce the production of TGF-β1 ( 73 ).…”

A comprehensive investigation on alleviating oxidative stress and inflammation in hyperglycaemic conditions through in vitro experiments and computational analysis

“…Increased AGEs generation is more common in diseases like diabetes mellitus (DM), which are linked to hyperglycemia ( Anwar et al, 2021a , Nowotny et al, 2015 ). AGEs may have noteworthy implications Xu et al (2023) , such as cardiovascular morbidities among individuals with diabetes mellitus, owing to their capability to connect intracellular and extracellular matrix proteins, alter tissue framework, functioning, and mechanical characteristics, and contribute to cellular processes by binding to cell surface receptors referred to as receptors for AGEs (RAGE) ( Taguchi & Fukami, 2023 ).…”

Glucose Fluctuation Inhibits Nrf2 Signaling Pathway in Hippocampal Tissues and Exacerbates Cognitive Impairment in Streptozotocin-Induced Diabetic Rats

“…Globally, the DM-related health expenditures were estimated at 966 billion USD in 2021, which are projected to reach 1,054 billion USD by 2045. DM can result in over 1 million deaths every year, becoming the ninth leading cause of death [4,5].…”