Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress

Department of Surgery, Columbia University, New York, New York, United States
Journal of Leukocyte Biology (Impact Factor: 4.3). 09/2007; 82(2):204-12. DOI: 10.1189/jlb.1206751
Source: PubMed

ABSTRACT The multiligand receptor for advanced glycation end products (RAGE) of the Ig superfamily transduces the biological impact of discrete families of ligands, including advanced glycation end products, certain members of the S100/calgranulin family, high mobility group box-1, Mac-1 (alpha(M)beta(2), CD11b/CD18), and amyloid-beta peptide and beta-sheet fibrils. Although structurally dissimilar, at least at the monomeric level, recent evidence suggests that oligomeric forms of these RAGE ligands may be especially apt to activate the receptor and up-regulate a program of inflammatory and tissue injury-provoking genes. The challenge in probing the biology of RAGE and its impact in acute responses to stress and the potential development of chronic disease is to draw the line between mechanisms that evoke repair versus those that sustain inflammation and tissue damage. In this review, we suggest the concept that the ligands of RAGE comprise a primal program in the acute response to stress. When up-regulated in environments laden with oxidative stress, inflammation, innate aging, or high glucose, as examples, the function of these ligand families may be transformed from ones linked to rapid repair to those that drive chronic disease. Identification of the threshold beyond which ligands of RAGE mediate repair versus injury is a central component in delineating optimal strategies to target RAGE in the clinic.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Aims Vascular complications are the major causes of morbidity and mortality in diabetic subjects. Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) induces signal transduction that culminates in vascular complications. Therefore; in the present study we investigated the dependence of RAGE expression on circulating AGEs and evaluated the outcome of AGE-RAGE interaction by the oxidative stress and nature of vascular complications in type 2 diabetes mellitus (T2DM) patients. Methods RAGE expression was determined by quantitative real-time PCR and western blotting, serum AGEs was estimated by ELISA and spectrofluorometry and oxidative stress markers namely protein carbonyl (PCO), advanced oxidation protein products (AOPP) and lipid peroxidation (MDA) were assayed spectrophotometerically in 75 T2DM patients (DM without vascular complication n = 25; DM with microvascular complications n = 25; DM with macrovascular complications n = 25) and 25 healthy controls. Results Serum AGEs level was significantly higher in diabetic patients having vascular complications as compared to T2DM without complications (p < 0.01). RAGE m-RNA expression level in PBMCs assayed by quantitative real time PCR was four times higher in diabetic subjects without vascular complications while DM patients having microvascular or macrovascular complications showed 12 fold and 8 fold higher RAGE m-RNA expression respectively compared to healthy controls. Circulating AGEs level showed significant positive correlation with RAGE m-RNA expression and oxidative stress markers. Conclusion AGE-mediated exacerbation of RAGE expression may contribute to oxidative stress generation that plays a key role in pathogenesis of vascular complications in diabetes.
    Microvascular Research 09/2014; 95. DOI:10.1016/j.mvr.2014.06.010 · 2.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The receptor for advanced glycation end-products (RAGE), a multi-ligand member of the immunoglobulin family, may play a crucial role in the regulation of lung fluid balance. We quantified soluble RAGE (sRAGE), a decoy isoform, and advanced glycation end-products (AGEs) from the BAL fluid of smokers and non-smokers, and tested the hypothesis that AGEs regulate lung fluid balance through PKC-gp91phox signaling to the epithelial sodium channel (ENaC). Human BAL samples from smokers showed increased AGEs (9.02 ±3.03 µg vs 2.48 ± 0.53µg), lower sRAGE (1205 ±292 pg/mL vs 1910 ±263 pg/mL) and lower volume(s) of epithelial lining fluid (ELF) (97 ±14 mL vs 133 ± 17 mL). In smokers, higher volumes of ELF were predicted with higher levels of sRAGE. Single channel patch clamp analysis of rat alveolar epithelial type 1 cells showed that AGEs increases ENaC NPo from 0.19 ± 0.08 to 0.83 ± 0.22 (P=0.017) and the subsequent addition of TEMPO decreased ENaC NPo to 0.15 ±0.07 (P=0.01). In type 2 cells, hAGEs increased ENaC NPo from 0.12 ± 0.05 to 0.53 ± 0.16 (P=0.025) and the addition of TEMPO decreased ENaC NPo to 0.10 ± 0.03 (P=0.013). Using molecular and biochemical techniques we observed that inhibition of RAGE and PKC activity attenuated AGEs-induced activation of ENaC. AGEs induced phosphorylation of p47phox and increased gp91phox dependent ROS production, a response that was abrogated with RAGE and PKC inhibition. Finally, tracheal instillation of AGEs promoted clearance of lung fluid while concomitant inhibition of RAGE, PKC and gp91phox abrogated the response.
    American Journal of Respiratory Cell and Molecular Biology 01/2014; DOI:10.1165/rcmb.2014-0002OC · 4.11 Impact Factor
  • Frontiers in Bioscience 01/2011; 16(1):486. DOI:10.2741/3700 · 4.25 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014