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Background: Chronic kidney disease (CKD) is characterized by an overproduction and accumulation of advanced glycation end products (AGEs). Because AGEs may play a role in the development of malnutrition and sarcopenia, two essential components of frailty, we evaluated whether they may also contribute to the onset of frailty in CKD patients. Methods: We performed a cross-sectional analysis of 117 patients. AGEs were quantified using a fluorescence spectrophotometer and soluble receptor for AGE (sRAGE) isoforms by ELISA. We defined frailty according to the frailty phenotype (FP) proposed by Fried. Results: The average age of patients was 80 ± 11 years, 70% were male, and the mean eGFR was 25 + 11 mL/min/1.73m2. Frailty was diagnosed in 51 patients, and 40 patients were classified as pre-frail. AGEs and RAGE isoforms seem not to correlate with overall frailty. Instead, AGEs were associated with specific frailty domains, inversely associated with BMI (R = −0.22, p = 0.016) and directly associated with gait test time (R = 0.17, p = 0.049). AGEs were also associated with involuntary weight loss (OR 1.84 p = 0.027), independent of age and sex. Conclusions: AGEs are associated with some pivotal components of the frailty phenotype, although they are not associated with frailty overall. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation end-products (RAGE) is expressed on human brain endothelial cells (HBEC) and is implicated in neuronal cell death after ischemia. We report that endogenous secretory RAGE (esRAGE) is a splicing variant form of RAGE that functions as a decoy against ischemia-induced neuronal cell damage. This study demonstrated that esRAGE was associated with heparan sulphate proteoglycans on HBEC. The parabiotic experiments between human esRAGE overexpressing transgenic (Tg), RAGE knockout (KO), and wild-type (WT) mice revealed a significant neuronal cell damage in the CA1 region of the WT side of parabiotic WT→WT mice, but not of Tg→WT mice, 7 days after bilateral common carotid artery occlusion. Human esRAGE was detected around the CA1 neurons in the WT side of the parabiotic Tg→WT pair, but not in the KO side of the Tg→KO pair. To elucidate the dynamic transfer of esRAGE into the brain, we used the blood-brain barrier (BBB) system (PharmaCo-Cell) with or without RAGE knockdown in endothelial cells. A RAGE-dependent transfer of esRAGE was demonstrated from the vascular to the brain side. These findings suggested that esRAGE is associated with heparan sulphate proteoglycans and is transferred into the brain via BBB to exert its neuroprotective effects in ischemia. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation end-products (RAGE) is expressed on human brain endothelial cells (HBEC) and is implicated in neuronal cell death after ischemia. We report that endogenous secretory RAGE (esRAGE) is a splicing variant form of RAGE that functions as a decoy against ischemia-induced neuronal cell damage. This study demonstrated that esRAGE was associated with heparan sulphate proteoglycans on HBEC. The parabiotic experiments between human esRAGE overexpressing transgenic (Tg), RAGE knockout (KO), and wild-type (WT) mice revealed a significant neuronal cell damage in the CA1 region of the WT side of parabiotic WT→WT mice, but not of Tg→WT mice, 7 days after bilateral common carotid artery occlusion. Human esRAGE was detected around the CA1 neurons in the WT side of the parabiotic Tg→WT pair, but not in the KO side of the Tg→KO pair. To elucidate the dynamic transfer of esRAGE into the brain, we used the blood-brain barrier (BBB) system (PharmaCo-Cell) with or without RAGE knockdown in endothelial cells. A RAGE-dependent transfer of esRAGE was demonstrated from the vascular to the brain side. These findings suggested that esRAGE is associated with heparan sulphate proteoglycans and is transferred into the brain via BBB to exert its neuroprotective effects in ischemia. [ABSTRACT FROM AUTHOR]

Our previous study showed that enhanced carbonyl stress is closely related to schizophrenia. The endogenous secretory receptor for advanced glycation end-products (esRAGE) is a splice variant of the AGER gene and is one of the soluble forms of RAGE. esRAGE is considered to be a key molecule for alleviating the burden of carbonyl stress by entrapping advanced glycation end-products (AGEs). In the current study, we conducted genetic association analyses focusing on AGER, in which we compared 212 schizophrenic patients to 214 control subjects. We also compared esRAGE levels among a subgroup of 104 patients and 89 controls and further carried out measurements of total circulating soluble RAGE (sRAGE) in 25 patients and 49 healthy subjects. Although the genetic association study yielded inconclusive results, multiple regression analysis indicated that a specific haplotype composed of rs17846798, rs2071288, and a 63 bp deletion, which were in perfect linkage disequilibrium (r 2 = 1), and rs2070600 (Gly82Ser) were significantly associated with a marked decrease in serum esRAGE levels. Furthermore, compared to healthy subjects, schizophrenia showed significantly lower esRAGE ( p = 0.007) and sRAGE ( p = 0.03) levels, respectively. This is the first study to show that serum esRAGE levels are regulated by a newly identified specific haplotype in AGER and that a subpopulation of schizophrenic patients are more vulnerable to carbonyl stress. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2010; 40 (7): 623–635 Background Cardiovascular disease is the major cause of death in patients with renal insufficiency, accounting for 50% of all deaths in renal replacement therapy patients. Mortality from cardiovascular diseases in these patients is approximately 9% per year, which is about 30 times the risk in the general population. So far, intensive interventions to the general risk factors, such as high LDL-cholesterol or C-reactive protein, have not been successful in improving their cardiovascular outcomes, suggesting that the beneficial effect of risk reduction may be overwhelmed by accumulated risk memorized by long-term exposure to oxidative stress during the progression of renal failure. Design In this review, we propose that this irreversible memory effect in renal failure may be mediated by advanced glycation end-products (AGEs). Results The generation of AGEs has been implicated to be deeply associated with increased oxidative stress. Moreover, interaction of the receptor for AGEs (RAGE) with AGEs leads to crucial biomedical pathway generating intracellular oxidative stress and inflammatory mediators, which could result in further amplification of the pathway involved in AGE generation. Several lines of evidence suggest that AGEs/RAGE axis can profoundly be involved in cardiovascular diseases. Recent advances in AGEs and RAGE measurements led us to be capable of understanding more about the role of AGEs/RAGE axis as a risk for cardiovascular diseases in patients with renal failure. Conclusion AGEs/RAGE axis could be a crucial mediator of oxidative stress in renal failure. RAGE could be not only a useful biomarker, but also a potentially therapeutic target to overcome the accumulated adverse metabolic memory in renal failure. [ABSTRACT FROM AUTHOR]

Receptor for advanced glycation endproducts (RAGE) is a cell-surface receptor. The binding of ligands to membrane-bound RAGE (mRAGE) evokes cellular responses involved in various pathological processes. Previously, we identified a novel soluble form, endogenous secretory RAGE (esRAGE) generated by alternative 5′ splice site selection in intron 9 that leads to extension of exon 9 (exon 9B). Because esRAGE works as an antagonistic decoy receptor, the elucidation of regulatory mechanism of the alternative splicing is important to understand RAGE-related pathological processes. Here, we identified G-rich cis-elements within exon 9B for regulation of the alternative splicing using a RAGE minigene. Mutagenesis of the G-rich cis-elements caused a drastic increase in the esRAGE/mRAGE ratio in the minigene-transfected cells and in loss of binding of the RNA motif to heterogenous nuclear ribonucleoprotein (hnRNP) H. On the other hand, the artificial introduction of a G-stretch in exon 9B caused a drastic decrease in the esRAGE/mRAGE ratio accompanied by the binding of hnRNP H to the RNA motif. Thus, the G-stretches within exon 9B regulate RAGE alternative splicing via interaction with hnRNP H. The findings should provide a molecular basis for the development of medicines for RAGE-related disorders that could modulate esRAGE/mRAGE ratio. [ABSTRACT FROM PUBLISHER]

The article focuses on a study that quantified the receptor for advanced glycation endproducts (RAGE) and its ligand, high-mobility group box-1 (HMGB1), in enchondromas and chondrosarcomas to determine whether these markers were associated with histological malignancy and prognosis. The results indicate that high expression of endogenous secretory RAGE in grade 1 chondrosarcoma was associated with subsequent recurrence, lung metastasis and poor survival.