Konečné produkty pokročilé glykace (advanced glycation end products – AGEs) hrají významnou roli v patogenezi řady chronických onemocnění a jejich komplikací, především diabetických komplikací, aterosklerózy, komplikací chronických onemocnění ledvin a neurodegenerativních onemocnění. Tyto látky vznikají neenzymatickou glykací a jejich tvorba je potencována vlivem karbonylového stresu. AGEs tvoří heterogenní skupinu látek a patří mezi ně např. karboxymetyllyzin, pentozin, metylglyoxallyzin dimer, vesperlyzin, imidazolony a další. AGEs jednak modifikují proteiny a mění jejich fyzikální a chemické vlastnosti, jednak mají účinky zprostředkované přes receptory, z nichž nejznámější, ale ne jediný, je receptor RAGE (receptor pro konečné produkty pokročilé glykace). RAGE je receptor multiligandový, váže také HMGB1 (high mobility group box protein 1), S100 proteiny či amyloidové fibrily. Vazba ligand na tento receptor má za následek aktivaci řady signálních cest včetně indukce oxidačního stresu a aktivace nukleárního faktoru κB a následnou prozánětlivou odpověď v závislosti na buněčném typu. AGEs a RAGE se spolu s dalšími mechanizmy – hexosaminovou cestou, polyolovou cestou, poruchou metabolizmu lipidů, aktivací proteinkinázy C, oxidačním stresem a zánětlivou reakcí spoluúčastní v patogenezi diabetických komplikací. Terapeuticky je možné snižovat endogenní tvorbu AGEs, ovlivnit přísun AGEs do organizmu stravou a jejich absorpci ve střevě či stimulovat jejich degradaci. Klíčová slova: AGEs – diabetes mellitus – karbonylový stres – konečné produkty pokročilé glykace – oxidační stres – RAGE – receptor pro AGEs – sRAGE – zánět

Advanced glycation end products (AGEs) play an important role in the pathogenesis of chronic diseases and their complications, especially diabetic complications, atherosclerosis, complications of chronic kidney diseases and neurodegenerative diseases. These substances are formed via non-enzymatic glycation and their formation is potentiated in case of carbonyl stress. AGEs are represented by a heterogeneous group of compounds, e.g. carboxymethyllysine, pentosine, methylglyoxallysin dimer, vesperlysine, imidazolones etc. AGEs can modify proteins and so change their physical and chemical properties and can act also via specific receptors, among them RAGE (receptor for advanced glycation end products) is the best known but not the unique one. RAGE is a multiligand receptor capable to bind also HMGB1 (high mobility group box protein 1), S100 proteins or amyloid fibrils. RAGE – ligand interactions results to activation of a variety of signaling pathways including oxidative stress and activation of nuclear factor κB and subsequent proinflammatory response depending on the cell type. AGEs and RAGE together with further mechanisms – hexosamine pathway, polyol pathway, lipid metabolism disorder, activation of proteinkinase C, oxidative stress and inflammatory reaction take part in the pathogenesis of diabetic complications. Terapeuticaly it is possible to decrease endogenous formation of AGEs, influence the AGEs intake to the organism and their absorption in the intestine or stimulate their degradation. Key words: AGEs – advanced glycation end-products – carbonyl stress – diabetes mellitus – inflammation – oxidative stress – RAGE – receptor for AGEs – sRAGE

• Klíčová slova
• karbonylový stres, sRAGE, receptor pro AGEs,
• MeSH
• diabetes mellitus etiologie   MeSH
• glykovaný hemoglobin fyziologie   MeSH
• lidé MeSH
• oxidační stres fyziologie   MeSH
• produkty pokročilé glykace * fyziologie   metabolismus   škodlivé účinky   MeSH
• receptory imunologické * biosyntéza   MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Úvod: Solubilní receptor pro konečné produkty pokročilé glykace (sRAGE) je inhibitorem toxických účinků konečných produktů pokročtlé glykace (Advanced Glycation End Products AGEs) zprostředkovaných přes RAGE. V běžné populaci, bez onemocnění ledvin, je sRAGE snížen u nemocných s ischemickou chorobou srdeční, s hypertenzí a u diabetiků. U nemocných s chronickým onemocněním ledvin je hladina sRAGE naopak zvýšená. Cíl: Porovnat hladinu sRAGE a sérových AGEs u obézních a neobézních nemocných s chronickým onemocněním ledvin (chronic kidney disease CKD) a při pravidelné hemodialýze (HD). Metody: Byly vyšetřeny 4 skupiny nemocných: 54 obézních s CKD, 47 neobézních s CKD, 31 obézních HD, 36 neobézních HD a 21 zdravých kontrol. Laboratorní metody. sRAGE (pg/ml) stanoveny pomocí ELISA kitů a sérové AGEs fluorimetricky (FI.IUIO3). Renalni funkce byla určována jako inulinová clearance. Statistické hodnocení: t-test Mann-Whitney test. korelace pomocí koeficientů dle Pearsona a Spearmana. Výsledky: Hladiny sAGEs jsou významně zvýšeny proti kontrolám u obézních i neobézních nemocných u CKD (548 ± 246, resp. 580 ± 266 versus 312.8 ± 39 u kontrol, p < 0,001) i u HD (1170 ± 320. resp. 1198 ± 256 versus 312.8 ± 139 u kontrol, p < 0.001), rozdíl mezi obézními a neobézními není statisticky významný. Naproti tomu sRAGE sice také stoupají ve srovnání s kontrolami (1390 ± 125), ale jsou významně nižší u obézních než u neobézních. a to jak u CKD (1646 ± 270 versus 2814 ± 116. p < 0,05), tak i u HD (2783 ± 290 versus 3773 ± 205, p < 0,05). Výsledky podporuje i zjištěná významná negativní korelace sRAGE s BMI (Body Mass Indexem) u nemocných s CKD (p < 0.001) i HD (p < 0,01). Záyěr: Solubilní receptor pro AGEs (s-RAGE) v séru nemocných s chronickým onemocněním ledvin a u HD nemocných stoupal současně se stoupajícími hladinami sérových AGEs. U obézních nemocných jsme však zjistili významně nižší hodnoty sRAGE než u neobézních. a to při srovnatelně vysoké hladině toxických AGEs. Ochranný vliv sRAGE je tedy u obézních nemocných menší a snížené hladiny sRAGE by bylo možno považovat za marker zvýšeného kardiovaskulárního rizika u těchto nemocných. Aktuality v nefrologii 2008; 14:15-19

Introduction: Soluble receptor for Advanced Glycation End Products (sRAGE) is a naturally occurring inhibitor of pathological effects mediated via RAGE. In the general population, protective sRAGE is decreased in patients with coronary artery disease, hypertens ion or diabetes mellitus. On the other hand, sRAGE levels are increased in patients with decreased renal function. Aim: The aim of the study was to compare the levels of sRAGE and serum Advanced Glycation End Products (sAGEs) in obese and non-obese patients with chronic kidney disease (CKD) and on hemodialysis (HD). Methods: Four groups of patients were examined: 54 obese CKD patients, 47 non-obese patients with CKD, 31 obese HD patients, 36 non-obese HD patients. Laboratory methods: sRAGE (pg/ml) were determined using ELISA kits and AGEs fluorimetrically (FI.IU × 10 3 ). Renal function was determined as inulin clearance. Statistical analysis: t-test, Mann-Whitney test, correlation using Pearson and Spearman coefficients. Results: Compared with controls, the levels of sAGEs are significantly increased in obese and non-obese CKD patients (548 ± 246 and 580 ± 266, respectively, versus 312.8 ± 39 in controls; p < 0.001) and in HD patients (1170 ± 320 and 1198 ± 256, respecti- vely, versus 312.8 ± 39 in controls; p < 0.001); the differences between the obese and non-obese are not significant. In contra st, sRAGE levels, while also increasing compared with controls (1390 ±125), are significantly lower in the obese compared with the non-obese, both with CKD (1646 ± 270 versus 2814 ± 116; p < 0.05) and with HD (2783 ± 290 versus 3773 ± 205; p < 0.05). The results are supported by the significant inverse correlation observed between sRAGE and BMI (Body Mass Index) in patients with CKD (p < 0.001) and HD (p < 0.01). Conclusion: The levels of soluble receptor pro AGEs (sRAGE) in the serum of patients with chronic kidney disease and in hemodi- alysis patients were increasing with increasing serum AGEs levels. However, the rise in obese patients was significantly smalle r compared with the non-obese at comparably high levels of toxic AGEs. Hence, the protective effect of sRAGE in obese patients is smaller, and the decreased levels of sRAGE could thus be considered the marker of increased cardiovascular risk in these patien ts.

• MeSH
• chronické selhání ledvin krev   patofyziologie   MeSH
• dialýza ledvin MeSH
• financování organizované MeSH
• hodnocení rizik metody   využití   MeSH
• kardiovaskulární nemoci prevence a kontrola   MeSH
• lidé MeSH
• muži MeSH
• obezita krev   patofyziologie   MeSH
• produkty pokročilé glykace analýza   diagnostické užití   krev   MeSH
• ženy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

It has been suggested that accumulation of advanced glycation end products (AGEs) is involved in several pathophysiological processes in the vessel wall. We hypothesized that low levels of the soluble receptor for AGEs (sRAGE) might be associated with increased arterial stiffness, a manifestation of vascular ageing in the general population. Using a cross-sectional design, we analyzed 1077 subjects from the Czech post-MONICA study. The aortic pulse wave velocity (aPWV) was measured using a Sphygmocor device. sRAGE concentrations were assessed in frozen samples using enzyme-linked immunosorbent assay methods (R&D Systems). aPWV significantly (P<0.0001) increased across the sRAGE quartiles. An aPWV of 1 m s(-1) was associated with a 37% increase in the risk of low sRAGE (<918 pg ml(-1), bottom quartile; P-value=0.018). In a categorized manner, subjects in the bottom sRAGE quartile had an odds ratio of an increased aPWV (⩾9.3 m s(-1)), adjusted for all potential confounders of 2.05 (95% confidence interval: 1.26-3.32; P=0.004), but this was only the case for non-diabetic hypertensive patients. In contrast, a low sRAGE was rejected as an independent predictor of an increased aPWV in normotensive or diabetic subjects using similar regression models. In conclusion, low circulating sRAGE was independently associated with increased arterial stiffness in a general population-based sample, but this was only observed in hypertensive non-diabetic patients.

• MeSH
• analýza pulzové vlny MeSH
• aorta patofyziologie   MeSH
• dospělí MeSH
• krevní tlak fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• průřezové studie MeSH
• receptor pro konečné produkty pokročilé glykace krev   MeSH
• senioři MeSH
• tuhost cévní stěny fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Receptor for advanced glycation end products and glyoxalase I metabolizing advanced glycation end product precursors may play important role in the pathogenesis and progression of cancer. Potential relation between soluble forms of receptor for advanced glycation end products (sRAGE), receptor for advanced glycation end products, glyoxalase I polymorphisms, and long-term outcome (median follow-up of 10.3 years) was studied in 116 patients with breast cancer. Gly82Ser and 2184 A/G RAGE polymorphisms were related to the mortality due to the breast cancer and -419 A/C glyoxalase I polymorphism was related to the overall mortality of the patients suggesting their role not only in the risk of breast cancer but also in the outcome of patients with breast cancer.

• MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus MeSH
• Kaplanův-Meierův odhad MeSH
• laktoylglutathionlyasa genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu genetika   mortalita   patologie   MeSH
• receptor pro konečné produkty pokročilé glykace genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Circulating levels of soluble receptor for advanced glycation end-products (sRAGE) have been suggested to have a protective role in neutralizing advanced glycation end-products (AGEs) and their pathological effects on vessel walls. We aimed to investigate the association between the circulating concentration of sRAGE and the dynamics of arterial wall stiffening as a manifestation of vascular aging in the general population. In a prospective cohort study, we longitudinally followed 530 general-population-based subjects (subsample of Czech post-MONICA study). Aortic pulse wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE were assessed at baseline by ELISA (R&D Systems). The average ∆PWV/year significantly decreased across the sRAGE quintiles (p = 0.048), and a drop by one sRAGE quintile was associated with an ~21% increase in the relative risk of accelerated age-dependent stiffening (∆PWV/year ≥ 0.2 m/s). Subjects in the bottom quintile of sRAGE (<889.74 pg/mL) had a fully adjusted odds ratio of accelerated stiffening of 1.72 (95% CI: 1.06-2.79), p = 0.028, while those with high sRAGE concentrations (≥1695.2 pg/mL) showed the opposite effect [odds ratio 0.55 (95% CI: 0.33-0.90), p = 0.017]. In conclusion, the circulating status of sRAGE independently influenced the individual progression of arterial stiffness over time. This finding strongly supports the hypothesis that high sRAGE has a protective role against vascular aging.

• MeSH
• analýza pulzové vlny MeSH
• dospělí MeSH
• krevní tlak fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• prospektivní studie MeSH
• receptor pro konečné produkty pokročilé glykace krev   MeSH
• senioři MeSH
• stárnutí metabolismus   MeSH
• tuhost cévní stěny fyziologie   MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• lidé MeSH
• parodontitida genetika   MeSH
• produkty pokročilé glykace genetika   MeSH
• receptory imunologické genetika   MeSH
• Check Tag
• lidé MeSH

The receptor for the advanced glycation end products (RAGE) is a multiligand transmembrane receptor involved in chronic inflammation whose specific polymorphisms of the promoter gene were found to increase its transcriptional activity. We investigated the association of both allelic and genotypic -374T/A and -429T/C polymorphisms with inflammatory bowel disease. The STREGA guidelines were applied for planning and reporting. We enrolled 133 patients with Crohn's disease (CD), 149 with ulcerative colitis (UC), and 128 blood donors. Genomic DNA was extracted from peripheral blood leukocytes collected from each patient and control. RAGE polymorphisms were analyzed by PCR-restriction fragment length polymorphism assay. The Hardy-Weinberg equilibrium was first assessed, and then, the Kruskal-Wallis test and the Fisher exact test were used for etiologic group comparisons. Distribution of patients' characteristics across genotypes was evaluated by the Fisher exact test, while that across alleles was analyzed with a probit model. A 2-sided value of p < 0.05 was considered significant. Following the evidence of the Hardy-Weinberg equilibrium, we found a higher prevalence of the allele A of the -374T/A haplotype in UC (p = 0.043), and of the allele C of the -429T/C haplotype in CD (p < 0.001) with respect to the other groups. Moreover, the homozygous AA genotype of the -374T/A polymorphism resulted associated with late onset of CD, while its TT genotype with early onset (p = 0.049). The allele C of the 429T/C haplotype was associated with early onset of UC (p = 0.03), while a higher frequency of the heterozygous TC haplotype was found in those with pancolitis (p = 0.026). The differing distribution of these polymorphisms in healthy donors and CD/UC patients suggests a role in the development and outcome of these pathological conditions.

• MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci * MeSH
• genotyp MeSH
• genotypizační techniky MeSH
• idiopatické střevní záněty genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• polymorfismus délky restrikčních fragmentů MeSH
• prevalence MeSH
• promotorové oblasti (genetika) * MeSH
• receptor pro konečné produkty pokročilé glykace genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Advanced glycation end products (AGEs) are involved in several pathophysiologic processes in vascular diseases, including progressive loss of elasticity of the vessel wall (arterial stiffness). Circulating soluble receptors for AGEs (sRAGE) act as a decoy and counterbalanced the harmful properties of AGEs as the natural protective factor. We compared the role of circulating or skin-deposed AGEs and sRAGE regarding the natural course of arterial stiffening. In a prospective cohort study, we longitudinally followed 536 general population-based subjects (subsample of Czech post-MONICA study). Aortic pulse-wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE and carboxymethyl lysine (circulating AGEs) were assessed at the follow-up visit by ELISA, while skin AGEs were measured using the autofluorescence-based device AGE Reader. Using multiple regressions, we found significant association between ∆PWV/year as a dependent variable, and both, sRAGE and skin AGEs as independent ones (each on its own model). However, the closest associations to ∆PWV/year were found for the ratio of these two factors (skin AGEs/sRAGE) [β coeff = 0.0747 (SE 0.0189), p < 0.0001]. In a categorized manner, subjects with skin AGEs/sRAGE ratio ≥ 3.3 showed about twofold higher risk having ΔPWV/year ≥ 0.2 m/s [adjusted odds ratio was 2.09 (95% CI: 1.35-3.22), p = 0.001]. In contrast, neither circulating AGEs nor circulating AGEs/sRAGE showed any significant relation to ΔPWV/year. In conclusion, skin AGEs/sRAGE ratio seems to be a more sensitive biomarker of vascular aging than these single factors themselves or circulation status of AGEs.

• MeSH
• biologické markery MeSH
• lidé MeSH
• produkty pokročilé glykace * MeSH
• prospektivní studie MeSH
• receptor pro konečné produkty pokročilé glykace MeSH
• stárnutí * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome. The aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. The authors studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and Her2/neu receptors) and in 92 healthy controls. Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 +/- 777 versus 1803 +/- 632 ng/mL, p < 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors, and intermediate positivity of Her2/neu receptors and were also influenced genetically (Gly82Ser and 2184 AG polymorphisms of the RAGE gene). Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression.

• MeSH
• dospělí MeSH
• financování organizované MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory prsu genetika   krev   MeSH
• polymorfismus genetický MeSH
• produkty pokročilé glykace krev   MeSH
• receptor erbB-2 analýza   MeSH
• receptory imunologické genetika   krev   MeSH
• receptory pro estrogeny analýza   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH

Endogenous secretory receptor (esRAGE) for advanced glycation end-product (AGE) acts as decoy for AGEs. The AGE-to-esRAGE ratio was hypothesized to be implicated in diabetic vasculopathy. We investigated an association of esRAGE and methylglyoxal-adducts serum level, as well as AGE-to-esRAGE ratio in subpopulation of diabetic patients with or without concomitant hyperlipidemia and macrovascular disease in history. In diabetes with concomitant hyperlipidemia esRAGE was significantly decreased compared to hyperlipidemia with normal glucose metabolism (0.306+/-0.2 vs. 0.367+/-0.1; p=0.019) or diabetes alone (0.306+/-0.2 vs. 0.404+/-0.1; p=0.004). High AGE/esRAGE ratio, found in diabetic patients with hyperlipidemia, pointed to increased production of AGEs and low expression of esRAGE. In multivariable analysis adjusted for several confounding factors, increased AGE/esRAGE ratio was recognized as a high risk for vascular disease outcomes.

• MeSH
• biologické markery krev   MeSH
• diabetes mellitus 2. typu krev   diagnóza   epidemiologie   MeSH
• dospělí MeSH
• hyperlipidemie krev   epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• produkty pokročilé glykace krev   MeSH
• receptory imunologické krev   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH