Article

Impact of hyperglycemia and acute pancreatitis on the receptor for advanced glycation endproducts

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  • Genics Pty Ltd
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Abstract

Since hyperglycemia aggravates acute pancreatitis and also activates the receptor for advanced glycation endproducts (RAGE) in other organs, we explored if RAGE is expressed in the pancreas and if its expression is regulated during acute pancreatitis and hyperglycemia. Acute pancreatitis was induced by cerulein in untreated and streptozotocin treated diabetic mice. Expression of RAGE was analyzed by Western blot and immunohistochemistry. To evaluate signal transduction the phosphorylation of ERK1/ERK2 was assessed by Western blot and the progression of acute pancreatitis was monitored by evaluation of lipase activity and the pancreas wet to dry weight ratio. RAGE is mainly expressed by acinar as well as interstitial cells in the pancreas. During acute pancreatitis infiltrating inflammatory cells also express RAGE. Using two distinct anti-RAGE antibodies six RAGE proteins with diverse molecular weight are detected in the pancreas, whereas just three distinct RAGE proteins are detected in the lung. Hyperglycemia, which aggravates acute pancreatitis, significantly reduces the production of two RAGE proteins in the inflamed pancreas.

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... Hyperglycemia can be both the result and the driver of inflammation and is associated with worse pancreatitis outcomes [35,36]. O-GlcNAcylation increases during times of hyperglycemia and increased nutrient flux through the HBP [37,38]. ...
... Hyperglycemia can be both the result and the driver of inflammation and is associated with worse pancreatitis outcomes [35,36]. O-GlcNAcylation increases during times of hy-perglycemia and increased nutrient flux through the HBP [37,38]. ...
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... However, our data in the present study suggested the relatively minor role of TLR4 in the development of pancreatic pain in the early stage of acute pancreatitis. Given evidence that pancreatic acinar cells express RAGE (Zechner et al. 2013), it is likely that the activation of RAGE by HMGB1 in the acinar cells as well as sensory nerves might be involved in the development of pancreatic pain. ...
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The aetiology of acute pancreatitis (AP) is complex, and many risk factors for AP are shared by patients with type 2 diabetes mellitus (T2DM). However, few have assessed risk factors for AP specifically in T2DM patients. Patients in the General Practice Research Database (2 984 755, 5.0% with T2DM) were used to estimate incidence of AP for T2DM relative to non-diabetes, adjusting for prior pancreatitis, gallbladder disease, obesity, smoking and alcohol use. Multivariate Cox regression analysis adjusting for risk factors and Charlson comorbidity index (CCI) was used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Between 2003 and 2007, 301 of 148 903 patients with T2DM and 2434 of almost 3 million patients without diabetes developed AP. Patients with T2DM had higher risk for AP compared with patients without diabetes (crude HR: 2.89, 95% CI: 2.56-3.27). Patients with T2DM had significantly higher rates of prior alcohol and tobacco exposure (44.2 and 61.9% vs. 34.1 and 35.9%, p < 0.001) and of comorbid conditions (14.7% with CCI > or =1 vs. 4.3%, p < 0.001). Histories of obesity, pancreatitis, gallbladder disease, smoking or alcohol use were significant predictors of AP. After adjusting for these factors, age, gender and comorbidities, the risk of developing AP remained elevated in patients with T2DM (adjusted HR: 1.49, 95% CI: 1.31-1.70). After adjusting for risk factors, patients with T2DM had an elevated risk of AP compared with patients without diabetes. Physicians should be aware of the increased risk in patients with T2DM, particularly in those with prior pancreatitis.
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Toll-like receptors (TLRs), a family of pattern recognition receptors, recognize and respond to conserved components of microbes and play a crucial role in both innate and adaptive immunity. In addition to binding exogenous ligands derived from pathogens, TLRs interact with endogenous molecules released from damaged tissues or dead cells and regulate many sterile inflammation processes. Putative endogenous TLR ligands include proteins and peptides, polysaccharides and proteoglycan, nucleic acids and phospholipids, which are cellular components, particularly extracellular matrix degradation products. Accumulating evidence demonstrates that endogenous ligand-mediated TLR signalling is involved in pathological conditions such as tissue injury, repair and regeneration; autoimmune diseases and tumorigenesis. The ability of TLRs to recognize endogenous stimulators appears to be essential to their function in regulating non-infectious inflammation. In this review, we summarize current knowledge of endogenous TLR ligands and discuss the biological significance of TLR signalling triggered by endogenous ligands in several sterile inflammation conditions.
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The RAGE binds multiple ligand families linked to hyperglycemia, aging, inflammation, neurodegeneration, and cancer. Activation of RAGE by its ligands stimulates diverse signaling cascades. The recent observation that the cytoplasmic domain of RAGE interacts with diaphanous or mDia-1 links RAGE signal transduction to cellular migration and activation of the Rho GTPases, cdc42 and rac-1. Pharmacological blockade of RAGE or genetic deletion of RAGE imparts significant protection in murine models of diabetes, inflammatory conditions, Alzheimer's disease, and tumors. Intriguingly, soluble forms of RAGE, including the splice variant-derived esRAGE, circulate in human plasma. Studies in human subjects suggest that sRAGE levels may be modulated by the diseases impacted by RAGE and its ligands. Thus, in addition to being a potential therapeutic target in chronic disease, monitoring of plasma sRAGE levels may provide a novel biomarker platform for tracking chronic inflammatory diseases, their severity, and response to therapeutic intervention.
Article
The receptor for advanced glycation end-products (RAGE) is thought to be expressed ubiquitously as various protein isoforms. Our objective was to use Northern blotting, immunoblotting, and sensitivity to N-glycanase digestion to survey RAGE isoforms expressed in cell lines and mouse tissues in order to obtain a more comprehensive view of the RAGE expressome. Pulmonary RAGE mRNA (1.4 kb) was smaller than cell-line and tissue RAGE mRNA (6 kb-10 kb). Three anti-RAGE antibodies that recognized three distinct RAGE epitopes were used for protein studies (N-16, H-300, and alphaES). Lung expressed three predominant protein isoforms with apparent molecular masses of 45.1, 52.6, and 57.4 kDa (N-16/H-300) and four isoforms at 25.0, 46.9, 52.5, and 54.2 kDa (alphaES). These isoforms were expressed exclusively in lung. Heart, ileum, and kidney expressed a 44.0-kDa isoform (N-16), whereas aorta and pancreas expressed a 53.3-kDa isoform (alphaES). Each of these isoforms were absent in tissue extracts prepared from RAGE(-/-) mice. Cell lines expressed a 70.0-kDa isoform, and a subset expressed a 30.0-kDa isoform (alphaES). Lung RAGE appeared to contain two N-linked glycans. Tissue and cell-line RAGE isoforms were completely insensitive to PNGase F digestion. Thus, numerous RAGE protein isoforms are detectable in tissues and cell lines. Canonical transmembrane and soluble RAGE appear to be expressed solely in lung (N-16/H-300). Non-pulmonary tissues and cell lines, regardless of the source tissue, both express distinct RAGE protein isoforms containing the N-terminal N-16 epitope or the alphaES RAGE epitope encoded by alternate exon 9, but lacking the H-300 epitope.
Article
A large retrospective autopsy study of patients was analyzed to evaluate the major etiologic and pathologic factors contributing to fatal acute pancreatitis (AP). From an autopsy population of 50,227 patients, 405 cases were identified where AP was defined as the official primary cause of death. AP was classified according to morphological and histological, but not biochemical, criteria. Patients with AP died significantly earlier than a control autopsy population of 38,259 patients. Sixty percent of the AP patients died within 7 days of admission. Pulmonary edema and congestion were significantly more prevalent in this group, as was the presence of hemorrhagic pancreatitis. In the remaining 40% of patients surviving longer than 7 days, infection was the major factor contributing to death. Major etiologic groups in AP were chronic alcoholism; postabdominal surgery; common duct stones; a small miscellaneous group including viral hepatitis, drug, and postpartum cases; and a large idiopathic group comprising patients with cholelithiasis, diabetes mellitus, and ischemia. The prevalence of established diabetes mellitus in the AP group was significantly higher than that observed in the autopsy control series, suggesting that this disease should be considered as an additional risk factor influencing survival in AP. Pulmonary complications, including pulmonary edema and congestion, appeared to be the most significant factor contributing to death and occurred even in those cases where the pancreatic damage appeared to be only moderate in extent. Emphasis placed on the early recognition and treatment of pulmonary edema in all cases of moderate and severe AP should contribute significantly to an increase in survival in this disease.
Article
Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.
Article
In this study we show that embryonic neurite growth-promoting protein amphoterin binds to carboxylated N -glycans previously identified on mammalian endothelial cells. Since amphoterin is a ligand for the receptor for advanced glycation end products (RAGE), and the ligand-binding V-domain of the receptor contains two potential N -glycosylation sites, we hypothesized that N -glycans on RAGE may mediate its interactions with amphoterin. In support of this, anti-carboxylate antibody mAbGB3.1 immunoprecipitates bovine RAGE, and PNGase F treatment reduces its molecular mass by 4.5 kDa, suggesting that the native receptor is a glycoprotein. The binding potential of amphoterin to RAGE decreases significantly in presence of soluble carboxylated glycans or when the receptor is deglycosylated. Oligosaccharide analysis shows that RAGE contains complex type anionic N -glycans with non-sialic acid carboxylate groups, but not the HNK-1 (3-sulfoglucuronyl beta1-3 galactoside) epitope. Consistent with the functional localization of RAGE and amphoterin at the leading edges of developing neurons, mAbGB3.1 stains axons and growth cones of mouse embryonic cortical neurons, and inhibits neurite outgrowth on amphoterin matrix. The carboxylated glycans themselves promote neurite outgrowth in embryonic neurons and RAGE-transfected neuroblastoma cells. This outgrowth requires full-length, signalling-competent RAGE, as cells expressing cytoplasmic domain-deleted RAGE are unresponsive. These results indicate that carboxylated N -glycans on RAGE play an important functional role in amphoterin-RAGE-mediated signalling.
Article
Previous studies suggested that blockade of RAGE in diabetic apolipoprotein (apo) E-null mice suppressed early acceleration of atherosclerosis. A critical test of the potential applicability of RAGE blockade to clinical settings was its ability to impact established vascular disease. In this study, we tested the hypothesis that RAGE contributed to lesion progression in established atherosclerosis in diabetic apoE-null mice. Male apoE-null mice, age 6 weeks, were rendered diabetic with streptozotocin or treated with citrate buffer. At age 14 weeks, certain mice were killed or treated with once-daily murine soluble RAGE or albumin; all mice were killed at age 20 weeks. Compared with diabetic mice at age 14 weeks, albumin-treated animals displayed increased atherosclerotic lesion area and complexity. In diabetic mice treated with sRAGE from age 14 to 20 weeks, lesion area and complexity were significantly reduced and not statistically different from those observed in diabetic mice at age 14 weeks. In parallel, decreased parameters of inflammation and mononuclear phagocyte and smooth muscle cell activation were observed. RAGE contributes not only to accelerated lesion formation in diabetic apoE-null mice but also to lesion progression. Blockade of RAGE may be a novel strategy to stabilize atherosclerosis and vascular inflammation in established diabetes.
Article
Acute pancreatitis is more common in childhood than has been appreciated previously. During acute attacks of pancreatitis, hyperglycaemia and glycosuria are not uncommon but permanent diabetes mellitus is rare. Acute pancreatitis can also be associated with diabetic ketoacidosis and the association between these two is of a two-way cause and effect relationship. Early imaging of the pancreas is recommended in children with severe prolonged abdominal pain.
Article
Chronic pancreatitis (CP) is considered to be a rare cause of diabetes mellitus. However, in both the developed and developing world, there is an increasing number of patients suffering from pancreatitis probably due to lifestyle changes, which is partially associated with both social factors and the poor health status of immigrants. Owing to these circumstances, CP has evolved with one of the possible causes of diabetes in a selected group of patients and should be included in the differential diagnosis of diabetes. Several studies have shown that the long-term rate of diabetic complications in patients with CP and insulin-dependent diabetes is similar to that in patients with type 1 diabetes of equal duration. The hypothesis that early diagnosis of CP should result in better prognosis is not validated and may complicate the issue, since the risk of diabetes has been shown to increase significantly only once pancreatic calcification has developed. Accumulative evidence suggests that the risk of diabetes is not influenced by elective pancreatic surgical procedures other than distal pancreatectomy. The lack of contemporary data points to the urgent need for large prospective studies in order to accurately evaluate the special characteristics of disorders in glucose homeostasis in patients with CP.
Article
The beneficial effects of reperfusion therapies have been limited by the amount of ischemic damage that occurs before reperfusion. To enable development of interventions to reduce cell injury, our research has focused on understanding mechanisms involved in cardiac cell death after ischemia/reperfusion (I/R) injury. In this context, our laboratory has been investigating the role of the receptor for advanced-glycation end products (RAGE) in myocardial I/R injury. In this study we tested the hypothesis that RAGE is a key modulator of I/R injury in the myocardium. In ischemic rat hearts, expression of RAGE and its ligands was significantly enhanced. Pretreatment of rats with sRAGE, a decoy soluble part of RAGE receptor, reduced ischemic injury and improved functional recovery of myocardium. To specifically dissect the impact of RAGE, hearts from homozygous RAGE-null mice were isolated, perfused, and subjected to I/R. RAGE-null mice were strikingly protected from the adverse impact of I/R injury in the heart, as indicated by decreased release of LDH, improved functional recovery, and increased adenosine triphosphate (ATP). In rats and mice, activation of the RAGE axis was associated with increases in inducible nitric oxide synthase expression and levels of nitric oxide, cyclic guanosine monophosphate (cGMP), and nitrotyrosine. These findings demonstrate novel and key roles for RAGE in I/R injury in the heart. The findings also demonstrate that the interaction of RAGE with advanced-glycation end products affects myocardial energy metabolism and function during I/R.
Article
Mortality in chronic pancreatitis is higher than in the general population, the 10-year survival after diagnosis is estimated between 69-80%. Evaluation of mortality risk factors in chronic pancreatitis. Eighty-two patients with chronic pancreatitis were followed-up for an average period of 25 months (median 25 months). None of them had an endoscopic treatment before inclusion in this study. The average age of the patients was 48 years (range 29 to 78, median 49), the ratio men:women being 6.5:1. The etiology was alcoholic in 84.2 % cases, pancreas divisum in 8.5% cases and idiopathic in 7.3% of cases. During the follow-up period the mortality rate was 17%, death occurring at on average 59 months (median 53 months) from the onset of the disease. The most frequent causes of death were: pancreatic cancer (3.6%), complications after surgery (3.6%) and upper digestive hemorrhage (2.4%). The mortality risk factors were presence of diabetes, no alleviation of pain under treatment and unceasing of smoking. The type of treatment applied did not influence survival. The cumulative survival rate estimated at 3 years was 80% and at 5 years 59%. The mortality rate in chronic pancreatitis was higher than those reported in the literature. Death caused by pancreatic cancer occurred in 3.6 % of the patients. There were no cases of death due to extra pancreatic cancers. The mortality risk factors were unceasing of smoking, no alleviation of pain under treatment and presence of diabetes.
Article
Early identification of patients at high risk of complications from acute pancreatitis is important; as yet, no simple and accurate method has been identified. The aim was to evaluate admission serum glucose as a prognostic marker in gallstone pancreatitis. Retrospective review of consecutive admissions with gallstone pancreatitis to a large urban hospital was made. Serum glucose levels, Glasgow scores, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were recorded. Outcomes considered were death, intensive care requirement, local complications, and length of hospital stay. There was a total of 184 admissions (122 women and 62 men; mean age, 55.4 years). Serum glucose of 8.3 mmol/L or higher was as good as APACHE II score of 8 or above (likelihood ratios [LRs] of 2.51 and 2.84, respectively) in predicting mortality (overall probability, 4.3%). Overall, 9.2% of the patients were admitted to intensive care units, and risk was significantly higher in patients with glucose of 8.3 mmol/L or higher (LR, 3.23; P < 0.001) or APACHE II score of 8 or above (LR, 1.9; P < 0.02). Local complications occurred in 12.0% of the patients, and the risk significantly increased in patients with glucose of 8.3 mmol/L or higher (LR, 2.61; P < 0.001) but not for APACHE II or Glasgow scores. Patients with admission serum glucose of 8.3 mmol/L or higher had a mean length of stay of 17.9 days as compared with 7.1 days for patients with admission serum glucose of less than 8.3 mmol/L (P < 0.001). In gallstone pancreatitis, an elevated admission serum glucose level offers more prognostic information than Glasgow and APACHE II scores.
Article
Early hyperglycemia in acute pancreatitis (AP) is a prognostic sign of severe attack. Obesity, another risk factor for severe AP, is associated with impaired glucose regulation. We hypothesized that obesity is related to early hyperglycemia in patients with severe AP. Forty-four patients with severe AP with organ failure and 127 control patients with AP (33 severe AP and 94 mild AP) but without organ failure were studied. Plasma glucose and patients' height and weight for calculation of body mass index (BMI) were measured at admission. Body mass index was higher in organ failure patients than in controls (median, 27.0 kg/m2 [interquartile range, 24.9-30.4 kg/m2] vs 25.2 kg/m2 [interquartile range, 23.3-27.9 kg/m2; P = 0.007). Glucose level correlated with BMI in organ failure patients (r = 0.463, P = 0.002) but not in controls (r = 0.096, P = 0.28). Eight (18%) organ failure patients and 7 (5.5%) controls had prior type 2 diabetes (P = 0.025). In a logistic regression model, admission glucose level was the only independent predictor of organ failure. Obesity may contribute to early hyperglycemia in patients with AP. Multivariate analysis indicated that obesity is not an independent risk factor for organ failure, but it correlates with early hyperglycemia, which may predispose to systemic complications in AP.
RAGE: therapeutic target and biomarker of the inflammatory response--the evidence mounts
  • R Ramasamy
  • Yan Sf
  • S Am
Ramasamy R, Yan SF and Am S. RAGE: therapeutic target and biomarker of the inflammatory response--the evidence mounts. J Leukocyte Biol 2009; 86: 505-512.
Identification, classification, and expression of RAGE gene splice variants
  • B I Hudson
  • C Am
  • E Harja
  • A Z Kalea
  • M Arriero
  • H Yang
  • P J Grant
  • S Am
Hudson BI, Am C, Harja E, Kalea AZ, Arriero M, Yang H, Grant PJ and Am S. Identification, classification, and expression of RAGE gene splice variants. FASEB J 2008; 22: 1572-1580.
Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene
  • A Z Kalea
  • N Reiniger
  • H Yang
  • M Arriero
  • S Am
  • B I Hudson
Kalea AZ, Reiniger N, Yang H, Arriero M, Am S and Hudson BI. Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene. FASEB J 2009; 23: 1766-1774.