"AGER" redirects here. For other uses, see Ager (disambiguation). Schematic of the relation between an immunoglobulin and RAGE Schematic of the RAGE gene and its products RAGE (receptor for advanced glycation endproducts), also called AGER, is a 35 kilodalton transmembrane receptor of the immunoglobulin super family which was first characterized in 1992 by Neeper et al. Its name comes from its ability to bind advanced glycation endproducts (AGE), which include chiefly glycoproteins, the glycans of which have been modified non-enzymatically through the Maillard reaction. In view of its inflammatory function in innate immunity and its ability to detect a class of ligands through a common structural motif, RAGE is often referred to as a pattern recognition receptor. RAGE also has at least one other agonistic ligand: high mobility group protein B1 (HMGB1). HMGB1 is an intracellular DNA-binding protein important in chromatin remodeling which can be released by necrotic cells passively and by active secretion from macrophages, natural killer (NK) cells and dendritic cells. The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation. Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors. Isoforms of the RAGE protein, which lack the transmembrane and the signaling domain (commonly referred to as soluble RAGE or sRAGE) are hypothesized to counteract the detrimental action of the full-length receptor and are hoped to provide a means to develop a cure against RAGE-associated diseases. Gene and polymorphisms The human RAGE gene lies within Continue reading >>
Rage, Diabetes, And The Nervous System.
Abstract Longstanding diabetes mellitus targets kidney, retina, and blood vessels, but its impact upon the nervous system is another important source of disability. Diabetic peripheral neuropathy is a serious complication of inadequately treated diabetes leading to sensory loss, intractable neuropathic pain, loss of distal leg muscles, and impairment of balance and gait. Diabetes has been implicated as a cause of brain atrophy, white matter abnormalities, and cognitive impairment and a risk factor for dementia. Recent studies have incriminated advanced glycation end products (AGEs) and their receptor (RAGE) in the pathogenesis of diabetic nervous system complications. The availability of RAGE knockout mice and a competitive decoy for AGEs, soluble RAGE (sRAGE), has advanced our knowledge of the RAGE-mediated signalling pathways within the nervous system. They also provide hope for a future novel intervention for the prevention of diabetes-associated neurological complications. This review will discuss current knowledge of diabetes- and RAGE-mediated neurodegeneration, involving the distal-most level of epidermal nerve fibers in skin, major peripheral nerve trunks, dorsal root ganglia, spinal cord, and brain. Continue reading >>
Rage Biology, Atherosclerosis And Diabetes
Diabetes is characterized by accelerated atherosclerosis with widely distributed vascular lesions. An important mechanism by which hyperglycaemia contributes to vascular injury is through the extensive intracellular and extracellular formation of AGEs (advanced glycation end products). AGEs represent a heterogeneous group of proteins, lipids and nucleic acids, irreversibly cross-linked with reducing sugars. AGEs are implicated in the atherosclerotic process, either directly or via receptor-mediated mechanisms, the most extensively studied receptor being RAGE (receptor for AGEs). The AGE–RAGE interaction alters cellular signalling, promotes gene expression and enhances the release of pro-inflammatory molecules. It elicits the generation of oxidative stress in numerous cell types. The importance of the AGE–RAGE interaction and downstream pathways leading to injurious effects as a result of chronic hyperglycaemia in the development, progression and instability of diabetic atherosclerotic lesions has been amply demonstrated in animal studies. Moreover, the deleterious link of AGEs with diabetic vascular complications has been suggested in many human studies. In the present review, our current understanding of their role as an important mediator of vascular injury through the various stages of atherosclerosis in diabetes will be reviewed and critically assessed. Abbreviations: ACE, angiotensin-converting enzyme; ADAM10, a disintegrin and metalloprotease 10; AGE, advanced glycation end product; apoE, apolipoprotein E; CML, N∊-(carboxymethyl)lysine; DCCT, Diabetes Control and Complications Trial; EPC, endothelial progenitor cell; ERK, extracellular-signal-regulated kinase; HbA1c, glycated haemoglobin; HMGB1, high-mobility group box protein 1; IL, interleukin; KO, knockou Continue reading >>
Receptor For Advanced Glycation End Products (rage) Deficiency Attenuates The Development Of Atherosclerosis In Diabetes
OBJECTIVE—Activation of the receptor for advanced glycation end products (RAGE) in diabetic vasculature is considered to be a key mediator of atherogenesis. This study examines the effects of deletion of RAGE on the development of atherosclerosis in the diabetic apoE−/− model of accelerated atherosclerosis. RESEARCH DESIGN AND METHODS—ApoE−/− and RAGE−/−/apoE−/− double knockout mice were rendered diabetic with streptozotocin and followed for 20 weeks, at which time plaque accumulation was assessed by en face analysis. RESULTS—Although diabetic apoE−/− mice showed increased plaque accumulation (14.9 ± 1.7%), diabetic RAGE−/−/apoE−/− mice had significantly reduced atherosclerotic plaque area (4.9 ± 0.4%) to levels not significantly different from control apoE−/− mice (4.3 ± 0.4%). These beneficial effects on the vasculature were associated with attenuation of leukocyte recruitment; decreased expression of proinflammatory mediators, including the nuclear factor-κB subunit p65, VCAM-1, and MCP-1; and reduced oxidative stress, as reflected by staining for nitrotyrosine and reduced expression of various NADPH oxidase subunits, gp91phox, p47phox, and rac-1. Both RAGE and RAGE ligands, including S100A8/A9, high mobility group box 1 (HMGB1), and the advanced glycation end product (AGE) carboxymethyllysine were increased in plaques from diabetic apoE−/− mice. Furthermore, the accumulation of AGEs and other ligands to RAGE was reduced in diabetic RAGE−/−/apoE−/− mice. CONCLUSIONS—This study provides evidence for RAGE playing a central role in the development of accelerated atherosclerosis associated with diabetes. These findings emphasize the potential utility of strategies targeting RAGE activation in the prevention and trea Continue reading >>
Review Articles The Rage Axis And Endothelial Dysfunction: Maladaptive Roles In The Diabetic Vasculature And Beyond
Receptor for advanced glycation end product (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. The ligand–RAGE axis is emerging as a central mechanism linked to vascular injury and atherosclerosis in diabetes and in euglycemia. The repertoire of RAGE ligands, including advanced glycation end products, S100/calgranulins, high-mobility group box 1, amyloid-β peptide, and Mac-1, transcends RAGE biology from specifically the science of diabetic complications to central aspects of the inflammatory response and oxidative stress. Experiments in cell culture and in vivo support the notion that interaction of RAGE ligands with RAGE activates key signal transduction pathways that modulate fundamental cellular properties, thereby leading to vascular and inflammatory cell perturbation. These considerations support the premise that the ligand–RAGE axis may be an important target for therapeutic intervention in cardiovascular disease and, fundamentally, in initiation and amplification of inflammatory responses. Continue reading >>
The Age-rage System And Diabetic Nephropathy.
Abstract As is diabetes itself, diabetic vasculopathy is a multifactor disease. Studies revealed advanced glycation end products (AGE) as the major environmental account for vascular cell derangement characteristic of diabetes and the receptor for AGE (RAGE) as the major genic factor that responds to them. AGE fractions that caused the vascular derangement were proved to be RAGE ligands. When made diabetic, RAGE transgenic mice exhibited the exacerbation of the indices of nephropathy and retinopathy, and this was prevented by the inhibition of AGE formation. Extracellular signals and nuclear factors that induce the transcription of human RAGE gene were also identified, which would be regarded as risk factors of diabetic complications. Through an analysis of vascular polysomal poly(A)(+)RNA, a novel splice variant coding for a soluble RAGE protein was found and was named endogenous secretory RAGE. Endogenous secretory RAGE was able to capture AGE ligands and to neutralize the AGE action on endothelial cells, suggesting that this variant has a potential to protect blood vessels from diabetes-induced injury. The AGE-RAGE system, therefore, should be a candidate molecular target for overcoming this life- and quality-of-life-threatening disease. Continue reading >>
Blocking “rage” Prevents Diabetic Atherosclerosis
New York, NY, September 21, 1998 — Researchers at Columbia University College of Physicians & Surgeons report that they have prevented the accelerated atherosclerosis associated with diabetes in mice by blocking activation of a cell-surface receptor called RAGE. Atherosclerosis is the major cause of death and disability for patients with diabetes and people with diabetes account for more than half of all heart attacks in the United States. The research, reported in the September issue of Nature Medicine, suggests that the discovery may provide the basis for new therapeutic strategy. Currently the only treatments for atherosclerosis associated with diabetes are control of blood sugar and conventional treatments for patients without diabetes. “Our research emphasizes a target that people didn’t consider before. RAGE looks like it is a candidate for future therapy,” says Dr. David Stern, professor of physiology and cell biophysics and surgery. Dr. Stern and Dr. Ann Marie Schmidt, assistant professor of surgical science and medicine, led the P&S research team. Although controlling blood-sugar levels, reducing weight, and lowering cholesterol can help fight blood-vessel disease, atherosclerosis, the buildup of fatty plaques inside blood vessels, remains a serious problem for patients with diabetes. No matter how carefully a patient with diabetes controls blood-sugar, levels are bound to rise above optimal at some point. When that occurs, the excess blood sugar reacts with proteins and lipids in a process similar to the browning of food to form molecules known as advanced glycation end products, or AGEs. In 1992, Drs. Schmidt and Stern reported the isolation of a cell-surface receptor on cells of the blood vessel wall to which the AGEs bound. They named it RAGE, for r Continue reading >>
Are People With Diabetes More Prone To Aggression?
Relationship Between Blood Glucose Level and Self-Control Blood sugar can make people do crazy things. According to a recent scientific study on the link between low blood glucose level and relationship clashes (Bushman et al, 2014), being hungry makes an individual generally cranky and act more hostile to others. In the study, couples who are hungry tend to have a much higher tendency to exhibit aggression towards each other and become more impulsive in their reactions. This phenomenon is often referred to “hangry” (meaning feeling angry when you are hungry). If this irritable state can happen to any healthy person who experiences a change in their blood glucose level, imagine the ordeals individuals with diabetes frequently go through on a daily basis. However, do not jump to the conclusion that diabetes leads to aggression. In fact, scientists find a more direct correlation between blood glucose level and self-control. I recommend reading the following articles: In a way, you can visualize self-control as a muscle that requires a lot of energy to sustain so that it does not become ineffective quickly. This energy source comes from the glucose in the blood. So what kind of activities can wear out this “muscle”? Any daily activities that require self-discipline such as forcing yourself to get out of bed early to exercise, resisting from having a soda drink or another cookie with your meal, stopping yourself from smoking, dealing with stressful situations at work and at home, and abstaining yourself from road rage. As you can see, self-control plays a crucial part in restraining inappropriate and aggressive behaviors. So when people are low in glucose, the self-control mechanism cannot function properly to prevent these outbursts of hostile actions. In a researc Continue reading >>
The Rage Axis In Early Diabetic Retinopathy
purpose. The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR). methods. The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E−/− db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade. results. Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice. conclusions. In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated a Continue reading >>
Did "diabetic Rage" Play Role In Texas Da Killings?
NORTH TEXAS - Less than a month after he was sentenced to death for the murders of a district attorney and the district attorney's wife, the state of Texas has agreed to have former Justice of the Peace Eric Williams examined to see if his murderous rampage was triggered by a damaged brain, reports CBS DFW. Williams' brain scan was scheduled for Thursday Jan. 8 at the University of Texas Medical Branch at Galveston, according to the station. While the test was initially denied by a judge, sources tell the station that defense lawyers pushed for the examination in hopes that it will show that health reasons, possibly caused by diabetes, affected Williams' brain, driving him to shoot and kill Kaufman County District Attorney Mike McLelland and his wife Cynthia, the night before Easter Sunday 2013. Last month, Williams was sentenced to death for the crimes. The judge who presided over his trial has since retired, leaving appeals to state District Judge Webb Biard of Paris, Texas, who ultimately granted Williams' wishes for a brain exam. Sources tell CBS DFW that defense lawyers hope that any medical proof that Williams is mentally disabled will result in the dismissal of the conviction and the need for a new trial. If that doesn't happen, the sources say, Williams is hoping the test results will at least lessen his punishment, sparing him from the death penalty. The McLellands' bullet-riddled bodies were found in their home in Forney, east of Dallas, two months after Mike McLelland's top prosecutor, Mark Hasse, was gunned down as he walked to the county courthouse in Kaufman. Williams is also charged with capital murder in Hasse's death. Prosecutors argued during his trial that Williams acted out of rage and revenge because Hasse and McLelland had prosecuted him for felony Continue reading >>
Long-term Renal Effects Of A Neutralizing Rage Antibody In Obese Type 2 Diabetic Mice
Advanced glycation end products (AGEs) have been implicated in the pathogenesis of diabetic kidney disease. The actions of AGEs are mediated both through a non–receptor-mediated pathway and through specific receptors for AGE (RAGEs). To explore a specific role for RAGE in renal changes in type 2 diabetes, we examined the renal effects of a neutralizing murine RAGE antibody in db/db mice, a model of obese type 2 diabetes. One group of db/db mice was treated for 2 months with the RAGE antibody, and another db/db group was treated for the same period with an irrelevant IgG. Two groups of nondiabetic db/+ mice were treated with either RAGE antibody or isotype-matched IgG for 2 months. Placebo-treated db/db mice showed a pronounced increase in kidney weight, glomerular volume, basement membrane thickness (BMT), total mesangial volume, urinary albumin excretion (UAE), and creatinine clearance compared with nondiabetic controls. In RAGE antibody–treated db/db mice, the increase in kidney weight, glomerular volume, mesangial volume, and UAE was reduced, whereas the increase in creatinine clearance and BMT was fully normalized. Notably, these effects in db/db mice were seen without impact on body weight, blood glucose, insulin levels, or food consumption. In conclusion, RAGE is an important pathogenetic factor in the renal changes in an animal model of type 2 diabetes. The prevalence of type 2 diabetes is increasing worldwide. The development of diabetic nephropathy is seen in up to 30–40% of all type 2 diabetic subjects followed by an increased morbidity and mortality. Furthermore, diabetic nephropathy is the most common cause of end-stage renal failure in the western world. Among the many potential pathogenic mechanisms responsible for the development of diabetic kidney Continue reading >>
Rage-mediated Inflammation, Type 2 Diabetes, And Diabetic Vascular Complication
Obesity is associated with an increased risk of developing type 2 diabetes, fatty liver disease, hypertension, and vascular complications (1). Proinflammatory and anti-inflammatory bioactive molecules produced from adipose tissues, known as adipokines, contribute to the burden of obesity-related diseases (2). Adipose tissue consists of heterogeneous populations of adipocytes, stromal preadipocytes, immune cells, and vascular cells, and it can respond rapidly and dynamically to alterations in nutrient excess caused by enhanced food consumption through adipocyte hypertrophy and hyperplasia (3). This results in a local inflammation in adipose tissue that propagates an overall systemic but chronic low-grade inflammation associated with the development of obesity-related comorbidities such as type 2 diabetes and cardiovascular diseases (2). Innate Immunity and RAGE-Mediated Inflammatory Reactions The innate immune system can act as a double-edged sword in protecting the host against foreign enemies and destroying tissues via inflammation. It may represent an evolutionary strategy adopted by multicellular organisms to prevent the survival of cells that would otherwise cause more disastrous consequences in the individuals and their descendants. Toll-like receptors (TLR) and receptor for advanced glycation end-products (RAGE) can participate in innate immunity maintaining a delicate balance between clearance of pathogens and induction of exaggerated inflammatory responses. Receptor for advanced glycation end-products is originally identified for recognizing advanced glycation end-products (AGE) (4). RAGE belongs to the immunoglobulin superfamily, and is now known as a member of pattern-recognition receptors (PRRs) and as a proinflammatory device. RAGE recognizes a variety of en Continue reading >>
Are Diabetics Angry...?
(See Also: Diabetes and Anger -- Is there a Deeper Connection?) This angry diabetic has been really bewildered for the past few weeks with many new and personal challenges... As we know, life's problems do not stop at diabetes, or any other chronic illness, nor do they care if we're having to juggle other things. In fact, in the storm of life... sometimes when it rains, it just pours. (I need to buy a raincoat.) So, I thought... why not take a little time to address a common, and often overlooked, issue with diabetes? Anger. In the past few weeks, my blog has registered many, many Google searches for "anger and diabetes," "do diabetics suffer from anger," "do diabetics need anger management," etc. I fear many of these folks might be family members really wanting to understand, and care for their loved ones... or maybe folks just wanting to understand themselves a little better. Before I get a little further into the discussion, I want to add that while the emotions we experience through the ups and downs of illness, and life, are perfectly normal... this blog post is in NO WAY a justification for aggression, violence, or abuse. It might be an EXPLANATION of a course of events, but in the end... we are responsible for our own selves, and how we manage our health, and our emotions. Got that? Okay... :) Diabetes is a PERVASIVE disease... Now, in order to make some of kind of sense of the emotions a person with diabetes might feel, we need to understand one thing: Diabetes is a PERVASIVE life change. It is one of the most pervasive life changes an 'afflicted' person will ever have to face. While it may not seem as such in the beginning stages (especially for type 2, and often during a "honeymoon phase" for a type 1), with time, an individual will soon become painfully aware Continue reading >>
Diabetic Always Have Bad/scary Tempers? Why?
Did you know that people who suffer from diabetes had awful tempers? Sometimes they are just scary to be with. They blow up at the smallest thing and it is probably better that you are not in the way when this happens. Have you heard of this? I would like to think that this is not true but I have met a few people who not only believe this but actually live by this. This is of great concern to me because as a person ‘newly’ diagnosed with diabetes and living with a young family, I do not want to become ill tempered and unapproachable. So where does this negative perception of people who have diabetes come from? How is it that their relationships got so bad? What can I do to ensure that I do not become that monster? There is an element of truth to the claims. In my opinion these only account for 20% of the cases. As sufferers of diabetes we suffer from hypos, hypers and stress. Hypers make me feel just generally unwell. Hypos make me unaware and a bit abrupt. Insulin therapy although good, is still far from ideal and puts the body under a certain amount of stress. This can make you feel ill at ease. These can have the effect of making people with diabetes seem irritable and short tempered. Let me provide an example. I initially suffered from frequent hypos. During a hypo I am undergoing damage control. I am trying to behave as normal as I can. During the hypo I am not aware of subtleties such as tone, body language etc.... The result is that I become a terse insensitive communicator. I have random bouts of hypers and hypos but I want to be seen as a normal person. So when I am having one of these symptoms I don’t tell anyone and just carry on as ‘normal’. You can get quite good at this. Often people around me are completely unaware of the situation. The result o Continue reading >>
Rage And Ages In Mild Cognitive Impairment Of Diabetic Patients: A Cross-sectional Study
Abstract Receptor for advanced glycation end products (AGEs; RAGE) binds to both AGEs and amyloid-beta peptides. RAGE is involved in chronic complications of type 2 diabetes and Alzheimer’s disease. We aimed to investigate the roles of RAGE, AGEs and the Gly82Ser polymorphism of RAGE in mild cognitive impairment (MCI) among type 2 diabetes patients. Of the 167 hospitalized type 2 diabetes patients recruited, 82 satisfied the diagnostic criteria for MCI, and 85 matched control individuals were classified as non-MCI. Demographic data were collected, and the soluble RAGE (sRAGE) concentrations, serum AGE-peptide (AGE-P) levels, RAGE Gly82Ser genotype and neuropsychological test results were examined. Results The MCI group exhibited a decreased sRAGE level (0.87±0.35 vs. 1.05±0.52 ng/ml, p<0.01) and an increased serum AGE-P level (3.54±1.27 vs. 2.71±1.18 U/ml, p<0.01) compared with the control group. Logistic regression analysis indicated that each unit reduction in the sRAGE concentration increased the MCI risk by 54% (OR 0.46[95% CI 0.22–0.96], p = 0.04) and that each unit increase in the AGE-P level increased the MCI risk by 72% in the type 2 diabetes patients (OR 1.72[95% CI 1.31–2.28], p<0.01). The serum sRAGE level was negatively correlated with the score on the trail making test-B (TMT-B) (r = -0.344, p = 0.002), which indicates early cognitive deficits related to diabetes. Moreover, the AGE-P level was positively correlated with multiple cognitive domains (all p<0.05). No significant differences in the neuropsychological test results or serum RAGE concentrations between the different RAGE genotypes or in the RAGE genotype frequencies between the MCI and control groups were identified (all p>0.05). The RAGE pathway partially mediates AGE-induced MCI in diab Continue reading >>