AGEs/sRAGE, a novel risk factor in the pathogenesis of end-stage renal disease

Abstract

Interaction of advanced glycation end products (AGEs) with its cell-bound receptor (RAGE) results in cell dysfunction through activation of nuclear factor kappa-B, increase in expression and release of inflammatory cytokines, and generation of oxygen radicals. Circulating soluble receptors, soluble receptor (sRAGE), endogenous secretory receptor (esRAGE) and cleaved receptor (cRGAE) act as decoy for RAGE ligands and thus have cytoprotective effects. Low levels of sRAGE and esRAGE have been proposed as biomarkers for many diseases. However sRAGE and esRAGE levels are elevated in diabetes and chronic renal diseases and still tissue injury occurs. It is possible that increases in levels of AGEs are greater than increases in the levels of soluble receptors in these two diseases. Some new parameters have to be used which could be an universal biomarkers for cell dysfunction. It is hypothesized that increases in serum levels of AGEs are greater than the increases in the soluble receptors, and that the levels of AGEs is correlated with soluble receptors and that the ratios of AGEs/sRAGE, AGEs/esRAGE and AGEs/cRAGE are elevated in patients with end-stage renal disease (ESRD) and would serve as an universal risk marker for ESRD. The study subject comprised of 88 patients with ESRD and 20 healthy controls. AGEs, sRAGE and esRAGE were measured using commercially available enzyme linked immune assay kits. cRAGE was calculated by subtracting esRAGE from sRAGE. The data show that the serum levels of AGEs, sRAGE, cRAGE are elevated and that the elevation of AGEs was greater than those of soluble receptors. The ratios of AGEs/sRAGE, AGEs/esRAGE and AGEs/cRAGE were elevated and the elevation was similar in AGEs/sRAGE and AGEs/cRAGE but greater than AGEs/esRAGE. The sensitivity, specificity, accuracy, and positive and negative predictive value of AGEs/sRAGE and AGEs/cRAGE were 86.36 and 84.88 %, 86.36 and 80.95 %, 0.98 and 0.905, 96.2 and 94.8 %, and 61.29 and 56.67 % respectively. There was a positive correlation of sRAGE with esRAGE and cRAGE, and AGEs with esRAGE; and negative correlation between sRAGE and AGEs/sRAGE, esRAGE and AGES/esRAGE, and cRAGE and AGES/cRAGE. In conclusion, AGEs/sRAGE, AGEs/cRAGE and AGEs/esRAGE may serve as universal risk biomarkers for ESRD and that AGEs/sRAGE and AGEs/cRAGE are better risk biomarkers than AGEs/esRAGE.

Identifying Synergistic Mechanisms of Multiple Ingredients in Shuangbai Tablets against Proteinuria by Virtual Screening and a Network Pharmacology Approach

“…VEGF-A, the most specific and prominent angiogenic factor of VEGF family, has been reported to be involved in the process of angiogenesis, migration, and proliferation of endothelial cells [8,88,103,104]. In addition, autocrine secretion of VEGF was caused by the interactions of AGEs and their receptor RAGE, which were new risk factors in the pathogenesis of end-stage renal disease [105,106]. In this background, betasitosterol was reported to inhibit the expression of VEGF in kidney cancer rats, protecting functions in renal tissues [107].…”

AGE–RAGE Stress, Stressors, and Antistressors in Health and Disease

“…[1][2][3][4][5][6][7][8][9][10][11] However, diabetes and chronic renal disease and their complications are associated with high levels of serum sRAGE. 9,13 One would have expected that high levels of sRAGE would have protected the development of diabetes, chronic kidney disease. The reason for this discrepancy may be due to the elevation of levels of AGEs greater than the elevation of serum levels of sRAGE.…”

“…The reason for this discrepancy may be due to the elevation of levels of AGEs greater than the elevation of serum levels of sRAGE. Prasad et al 9,13 have reported that in the end-stage renal disease there is an increase in levels of both AGEs and sRAGE more so in AGEs than sRAGE. 9 It has been reported by Zhou et al 96 that the levels of AGEs and RAGE in carotid arterial wall are elevated in Zucker diabetic rats.…”

“…Prasad et al 9,13 have reported that in the end-stage renal disease there is an increase in levels of both AGEs and sRAGE more so in AGEs than sRAGE. 9 It has been reported by Zhou et al 96 that the levels of AGEs and RAGE in carotid arterial wall are elevated in Zucker diabetic rats. They also showed that the balloon injury in carotid artery of these rats further increased the levels of AGE and RAGE and produced neointimal hyperplasia.…”

“…13 Increased ratio of AGE/sRAGE has been implicated in pathogenesis of restenosis following PCI 98 hyperthyroidism, 7 and end-stage renal disease. 9 The sensitivity, specificity, positive and negative predictive value, and accuracy of AGE/sRAGE should be determined with large number of control and a particular group of patients. Using receiver operating characteristics (ROC) curve analysis, we have reported that the sensitivity and specificity of AGE/sRAGE ratio were 73% and 70%, respectively, in identifying patients with hyperthyroidism.…”