Advanced glycation end products (AGEs) and their receptor (RAGE) system in diabetic retinopathy

Vascular complications are a leading cause of blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. There is a growing body of evidence that formation and accumulation of advanced glycation end products (AGEs) progress during normal aging, and at an extremely accelerated rate in diabetes, thus being involved in the pathogenesis of diabetic vascular complications. Furthermore, the interaction by AGEs of their receptor, RAGE, activates down-stream signaling and evokes inflammatory responses in vascular wall cells. Therefore, inhibition of AGE formation or blockade of the RAGE signaling may be a promising target for therapeutic intervention to prevent diabetic vascular complications. This review discusses the molecular mechanisms of diabetic retinopathy, especially focusing on the AGE-RAGE system. Several types of inhibitors of the AGE-RAGE system and their therapeutic implications are also reviewed here.     

Receptor for advanced glycation end products (RAGE): a novel therapeutic target for diabetic vascular complication

Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Although several hyperglycemia-elicited metabolic and hemodynamic derangements have been implicated in the pathogenesis of diabetic vascular complication, the process of formation and accumulation of advanced glycation end products (AGEs) and their mode of action are most compatible with the theory 'hyperglycemic memory'. Further, there is a growing body of evidence that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of diabetic vascular complication. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells, thus playing an important role in the development and progression of diabetic micro- and macroangiopathy. These observations suggest that down-regulation of RAGE expression or blockade of the RAGE downstream signaling may be a promising target for therapeutic intervention in diabetic vascular complication. In this review, we discuss several types of agents that could potentially inhibit RAGE expression or its downstream pathways and their therapeutic implications in diabetic vascular complication.     

Advanced glycation end products and insulin resistance

Non-enzymatic modification of proteins by reducing sugars, a process that is also known as Maillard reaction, leads to the formation of advanced glycation end products (AGEs) in vivo. There is a growing body of evidence that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, thus being involved in the pathogenesis of diabetic vascular complications. Further, recently, engagement of their receptor, RAGE with AGEs is shown to activate its down-stream signaling and evoke oxidative stress and inflammation in diabetes. Since oxidative stress generation and inflammation are closely associated with insulin resistance as well, it is conceivable that the AGEs-RAGE system could play a role in the pathogenesis of insulin resistance and subsequently the development of diabetes. In this paper, we review the role of the AGEs-RAGE system in insulin resistance, especially focusing on its effects on the insulin-signaling pathways in skeletal muscles and adipocytes.     

Role of advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic microangiopathy

Diabetic vascular complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Chronic hyperglycemia is essentially involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic derangements. In this review, we discuss the molecular mechanisms of diabetic retinopathy and nephropathy, especially focusing on advanced glycation end products (AGEs) and their receptor (RAGE) system. Several types of AGE inhibitors and their therapeutic implications in diseases, including diabetic microangiopathy, will be discussed in the next review article.     

Advanced Glycation End Products and Diabetic Complications

During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.     

Nifedipine inhibits gene expression of receptor for advanced glycation end products (RAGE) in endothelial cells by suppressing reactive oxygen species generation

Advanced glycation end products (AGEs), the senescent macroprotein derivatives that form in increased amounts in diabetes, have been implicated in the pathogenesis of diabetic vascular complications. Indeed, AGEs elicit oxidative stress generation in vascular wall cells through an interaction with their receptor (RAGE), thus playing an important role in vascular inflammation and altered gene expression of growth factors and cytokines. We have previously shown that nifedipine, one of the most popular dihydropyridine-based calcium antagonists, blocked tumor necrosis factor-alpha-induced monocyte chemoattractant protein-1 expression in endothelial cells (ECs) through its antioxidative properties. However, the effects of nifedipine on AGE-exposed ECs remain to be elucidated. In this study we investigated whether nifedipine could inhibit the AGE-induced reactive oxygen species (ROS) generation and subsequent RAGE gene expression in human umbilical vein endothelial cells (HUVEC). Nifedipine completely inhibited AGE-induced ROS generation in HUVEC. Furthermore, nifedipine was found to prevent up-regulation of RAGE mRNA levels in AGE-exposed HUVEC. These results demonstrate that nifedipine can inhibit RAGE overexpression in AGE-exposed ECs by suppressing ROS generation. Our present study suggests that nifedipine may have therapeutic potential in the treatment of patients with AGE-related disorders such as diabetic vascular complications.     

Food-derived advanced glycation end products (AGEs): a novel therapeutic target for various disorders

Non-enzymatic modification of proteins by reducing sugars, a process that is also known as Maillard reaction, leads to the formation of advanced glycation end products (AGEs) in vivo. It is now well established that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, thus being implicated in various types of AGE-related disorders such as diabetic vascular complications, neurodegenerative diseases and cancers. Further, there is accumulating evidence that AGEs and their receptor RAGE interaction elicits oxidative stress generation and subsequently alters gene expression in various types of cells. In addition, digested food-derived AGEs are found to play an important role in the pathogenesis of the AGE-related disorders as well. Indeed, restriction of diet-derived AGEs not only blocks the progression of atherosclerosis and renal injury, but also improves insulin resistance in animal models. AGE-poor diets reduce serum levels of inflammatory biomarkers in patients with diabetes or chronic renal failure. These observations suggest that the restriction of food-derived AGEs or the inhibition of absorption of dietary AGEs may be a novel target for therapeutic intervention in the AGE-related disorders. In this paper, we review the pathological role of food-derived AGEs in various types of disorders and discuss the potential utility of oral adsorbent that inhibits the absorption of AGEs in these devastating diseases.     

The diverse ligand repertoire of the receptor for advanced glycation endproducts and pathways to the complications of diabetes

The multi-ligand receptor RAGE was discovered on account of its ability to bind and transduce the cell stress-provoking signals of advanced glycation endproducts (AGEs). The finding that RAGE also bound pro-inflammatory molecules set the stage for linking RAGE and inflammation to the pathogenesis of diabetic macro- and microvascular complications. In this review, we focus on the roles of RAGE and its ligands in diabetes complications. We recount the findings from mice, rats, swine and human subjects suggesting that RAGE action potently contributes to vascular, inflammatory and end-organ stress and damage in types 1 and 2 diabetes. We detail the efforts to track ligands and RAGE in human subjects with diabetes to address if this axis may be a biomarker reflective of the state of the diabetic complications. Lastly, we suggest specific strategies to tackle AGE–ligand–RAGE interactions as potential therapeutic targets for diabetes and its complications.     

The diverse ligand repertoire of the receptor for advanced glycation endproducts and pathways to the complications of diabetes

The multi-ligand receptor RAGE was discovered on account of its ability to bind and transduce the cell stress-provoking signals of advanced glycation endproducts (AGEs). The finding that RAGE also bound pro-inflammatory molecules set the stage for linking RAGE and inflammation to the pathogenesis of diabetic macro- and microvascular complications. In this review, we focus on the roles of RAGE and its ligands in diabetes complications. We recount the findings from mice, rats, swine and human subjects suggesting that RAGE action potently contributes to vascular, inflammatory and end-organ stress and damage in types 1 and 2 diabetes. We detail the efforts to track ligands and RAGE in human subjects with diabetes to address if this axis may be a biomarker reflective of the state of the diabetic complications. Lastly, we suggest specific strategies to tackle AGE-ligand-RAGE interactions as potential therapeutic targets for diabetes and its complications.     

Advanced glycation end products (AGEs) and their involvement in liver disease

Advanced glycation end products (AGEs) are a heterogeneous group of molecules, formed in vivo both by non-oxidative and oxidative reactions of sugars and their adducts to proteins and lipids. It is now well established that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, thus being implicated in various types of AGEs-related disorders such as diabetic vascular complications, neurodegenerative diseases and cancers. There is a growing body of evidence that activation of RAGE (receptor for AGEs) system is also implicated in these devastating disorders. Indeed, the engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory responses in various types of cells including hepatocytes and hepatic stellate cells. Liver is not only a target organ, but also an important site for clearance and catabolism of circulating AGEs. Although there are several papers to suggest the involvement of AGEs-RAGE system in various types of liver diseases such as non-alcoholic steatohepatitis, liver cirrhosis and cancers, as far as we know, there are few comprehensive reviews to deal with this issue. Therefore, in this paper, we shortly review the pathological role of AGEs and RAGE in various liver diseases.     

Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the major constituents of which are amyloid betaprotein and tau protein, respectively. Advanced glycation end-products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under normal aging, can be identified immunohistochemically in both SPs and NFTs in AD patients. Further, recent clinical evidence has suggested diabetes mellitus as one of the risk factors for the development and progression of AD. Continuous hyperglycemia is a causative factor for diabetic vascular complications, and it enhances the generation of AGEs through the non-enzymatic glycation, thereby being involved in the pathogenesis of AD as well. Moreover, there is a growing body of evidence to show that the interaction of AGEs with a receptor for AGEs (RAGE) elicits reactive oxygen species generation and vascular inflammation, and subsequently alters various gene expressions in numerous types of cells, all of which could contribute to the pathological changes of diabetic vascular complications and AD. Indeed, we have recently found that glyceraldehyde-derived AGEs (Glycer-AGE) induce apoptotic cell death in cultured cortical neuronal cells. In addition, we also found that neurotoxic effect of diabetic serum on neuronal cells was blocked by neutralizing antibody raised against Glycer-AGE. In human AD brains, Glycer-AGE are actually detected in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. These observations suggest that Glycer-AGE play a role in the pathogenesis of AD. In this review, we discuss the pathophysiological role for AGEs in the development and progression of AD, especially focusing on Glycer-AGE.     

Regulation of advanced glycation end product (AGE)-receptor (RAGE) system by PPAR-gamma agonists and its implication in cardiovascular disease

Non-enzymatic modification of proteins by reducing sugars leads to the formation of advanced glycation end products (AGEs), whose process has been reported to progress under physiological aging, oxidative stress or diabetic conditions. There is a growing body of evidence that AGEs and their receptor (RAGE) axis is involved in the pathogenesis of cardiovascular disease (CVD). Indeed, engagement of RAGE with AGEs is shown to elicit oxidative stress generation and subsequently evoke inflammatory and thrombogenic responses in various types of cells, including endothelial cells, smooth muscle cells, macrophages and renal cells, thus playing an important role in the development and progression of vascular injury in both diabetes and non-diabetes. These observations suggest that the inhibition of AGE formation, down-regulation of RAGE expression or blockade of the RAGE downstream signaling may be a promising therapeutic target for preventing CVD. Recently, peroxisome proliferator-activated receptor-γ (PPARγ) is involved in not only adipocyte differentiation, but also vascular homeostasis. Therefore, in this study, we review effects of PPARγ agonists on the AGE–RAGE system and their implication in CVD.     

Agents that block advanced glycation end product (AGE)-RAGE (receptor for AGEs)-oxidative stress system: a novel therapeutic strategy for diabetic vascular complications

Background: Diabetic vascular complications are leading causes of acquired blindness, end-stage renal failure, a variety of neuropathies, and accelerated atherosclerosis, which together could account for disabilities and high mortality rates in patients with diabetes. Since there is accumulating evidence that the advanced glycation end product (AGE)–RAGE (receptor for AGEs)–oxidative stress axis is involved in diabetic vascular complications, inhibition of the AGE–RAGE system may be a promising target for therapeutic intervention in these devastating disorders. Objective: In this review, we discuss several types of agent that may be able to inhibit the AGE–RAGE–oxidative stress system, and their therapeutic implications in vascular complications in diabetes. Methods: We have analyzed currently available scientific literature in the field of AGE–RAGE to create a comprehensive review on novel therapeutic agents for vascular complications in diabetes. Results/conclusion: Inhibition of AGE formation, blockade of the AGE–RAGE interaction, and suppression of RAGE expression or its downstream pathways may be novel therapeutic strategies for the treatment of vascular complications in diabetes.     

AGE-RAGE系统与糖尿病足综合征的发病机制及治疗进展

糖尿病足综合征（DFS）是糖尿病严重慢性并发症之一,其发病机制至今尚未完全阐明。晚期糖基化终末产物（AGEs）的形成参与DFS的发生、发展,AGEs与AGEs受体（RAGE）相互作用,并通过一系列分子机制导致糖尿病神经病变和外周血管病变。因此,抑制AGEs形成或阻断AGEs与其受体相互作用可以延缓糖尿病足的发生、发展。本文就AGEs形成、AGE-RAGE系统在DFS中的作用和DFS的治疗进展等作一综述。     

Advanced glycation end product (age) inhibitors and their therapeutic implications in diseases

Nonenzymatic modification of proteins by reducing sugars, a process that is also known as the Maillard reaction, leads to the formation of advanced glycation end products (AGEs) in vivo. There is a growing body of evidence that formation and accumulation of AGEs progress during normal aging, and at an extremely accelerated rate under diabetes, and are thus involved in the pathogenesis of various diseases such as diabetic vascular complications and neurodegenerative diseases. Therefore, inhibition of AGE formation may be a promising target for therapeutic intervention in AGE-related disorders. In this review, we discuss several types of AGE inhibitors and their therapeutic implications in diseases.     

RAGE: A Novel Target for Drug Intervention in Diabetic Vascular Disease

At high levels as seen in diabetes, glucose reacts with and forms adducts (advanced glycation end products; AGEs) on macromolecules including proteins and DNA, eliciting cellular dysfunction and leading to vascular disease. The major means is through cellular receptors; the best characterized is the receptor for advanced glycation end products (RAGE). Accumulation of both AGE/RAGE in addition to other identified ligands of RAGE, including S100/calgranulins, is the hallmark of this receptor in disease pathogenesis. Blockade of ligand-receptor interaction directly at the protein level, or transgenetically, prevents development of micro vascular (nephropathy) and macro vascular (atherosclerosis/restenosis) disease in small animal models. Furthermore, allelic variants of RAGE exist that alter the protein function and gene expression, which may further affect disease outcome. In conclusion, RAGE is a target for drug development to prevent vascular disease in diabetic and nondiabetic subjects.     

Protective role of sulphoraphane against vascular complications in diabetes

Context Diabetes is a global health challenge. Although large prospective clinical trials have shown that intensive control of blood glucose or blood pressure reduces the risk for development and progression of vascular complications in diabetes, a substantial number of diabetic patients still experience renal failure and cardiovascular events, which could account for disabilities and high mortality rate in these subjects.

Objective Sulphoraphane is a naturally occurring isothiocyanate found in widely consumed cruciferous vegetables, such as broccoli, cabbage and Brussels sprouts, and an inducer of phase II antioxidant and detoxification enzymes with anticancer properties. We reviewed here the protective role of sulphoraphane against diabetic vascular complications.

Methods In this review, literature searches were undertaken in Medline and in CrossRef. Non-English language articles were excluded. Keywords [sulphoraphane and (diabetes, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, diabetic complications, vascular, cardiomyocytes, heart or glycation)] have been used to select the articles.

Results There is accumulating evidence that sulphoraphane exerts beneficial effects on vascular damage in both cell culture and diabetic animal models via antioxidative properties. Furthermore, we have recently found that sulphoraphane inhibits in vitro formation of advanced glycation end products (AGEs), suppresses the AGE-induced inflammatory reactions in rat aorta by reducing receptor for AGEs (RAGE) expression and decreases serum levels of AGEs in humans.

Conclusion These findings suggest that blockade of oxidative stress and/or the AGE-RAGE axis by sulphoraphane may be a novel therapeutic strategy for preventing vascular complications in diabetes.     

The AGE/RAGE axis in diabetes-accelerated atherosclerosis

1. There is increasing evidence that advanced glycation end-products (AGEs) and their interaction with the receptor RAGE play a pivotal role in atherosclerosis, in particular in the setting of diabetes. 2. Previous studies have shown that inhibition of AGE accumulation and RAGE expression in diabetes by either reduction of the formation of AGEs or cross-link breakers was associated with reduced atherosclerosis and renal disease. Advanced glycation end-products bind to RAGE, thereby leading to activation of a range of inflammatory and fibrotic pathways causing tissue injury. Different splice variants of RAGE exist, including a soluble form that lacks the intracellular domain and fails to induce signal transduction. Therapeutic approaches using soluble RAGE as a decoy binding protein for circulating AGE have been effective in preventing externally induced arterial injury and atherosclerosis in the absence and presence of diabetes. 3. In order to delineate the role of RAGE in vascular disease in more detail, it was necessary to create RAGE(-/-) mice, as well as transgenic mice overexpressing RAGE in endothelial cells. It was shown that RAGE overexpression was associated with increased vascular injury, nephropathy and retinopathy. 4. In contrast, RAGE deletion was associated with partial vascular protection, such as reduced neointima formation after arterial denudation, as well as protection from diabetic nephropathy. The present review summarizes the evidence for RAGE being a pro-inflammatory and pro-fibrotic receptor. 5. Further studies are needed to delineate the effect of RAGE deletion and overexpression in diabetic macrovascular disease. Based on these findings, RAGE could be a potential therapeutic target in combating inflammatory vascular diseases, including diabetes-associated atherosclerosis.     

Role of advanced glycation end products (AGEs) in osteoporosis in diabetes

Recent meta-analyses have revealed that the risk of bone fracture is increased in both type 1 and type 2 diabetic patients. Low bone mineral density (BMD) can not necessarily explain the link, because BMD is increased rather than decreased in type 2 diabetes, while it is consistently low in type 1 diabetes subjects. Although multiple factors could influence the quality of bone and increase the bone fragility in diabetes, there is accumulating evidence for the association between osteoporosis and vascular calcification, which is an independent predictor of cardiovascular disease morbidity and mortality. Advanced glycation end products (AGEs) are formed by a non-enzymatic reaction between aldehydes of reducing sugars and the amino groups of proteins, lipids and nucleic acids that could contribute to the aging of macromolecules. The formation and accumulation of AGEs have been known to progress at an accelerated rate under diabetes. There is a growing body of evidence that AGEs and their receptor (RAGE) system elicit oxidative stress generation and subsequently evoke inflammatory responses in vascular wall cells, osteoblasts and osteoclasts, thereby being involved in both vascular calcification and osteoporosis in diabetes. Further, cross-linking in the organic bone matrix by AGEs could adversely affect the fracture resistance of bone. Therefore, in this paper, I review the pathophysiological role of the AGEs-RAGE-oxidative stress system in decreased BMD and increased bone fragility in diabetes. I also discuss here the potential therapeutic interventions of the AGEs-RAGE axis for preventing osteoporosis in diabetes.     

The multifaceted therapeutic potential of benfotiamine

Thiamine, known as vitamin B₁, plays an essential role in energy metabolism. Benfotiamine (S-benzoylthiamine O-monophoshate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation transketolase, resulting in the reduction of tissue level of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications. Chronic hyperglycemia accelerates the reaction between glucose and proteins leading to the formation of AGEs, which form irreversible cross-links with many macromolecules such as collagen. In diabetes, AGEs accumulate in tissues at an accelerated rate. Experimental studies have elucidated that binding of AGEs to their specific receptors (RAGE) activates mainly monocytes and endothelial cells and consequently induces various inflammatory events. Moreover, AGEs exaggerate the status of oxidative stress in diabetes that may additionally contribute to functional changes in vascular tone control observed in diabetes. The anti-AGE property of benfotiamine certainly makes it effective for the treatment of diabetic neuropathy, nephropathy and retinopathy. Interestingly, few recent studies demonstrated additional non-AGE-dependent pharmacological actions of benfotiamine. The present review critically analyzed the multifaceted therapeutic potential of benfotiamine.