doi: 10.1161/ATVBAHA.107.144337
© 2007 American Heart Association, Inc.
Letters to the Editor |
Assaying Soluble Forms of Receptor for Advanced Glycation End Products
Department of Biochemistry and Molecular Vascular Biology (Y.Y., S.S., T.W., H. Yamamoto), Kanazawa University Graduate School of Medical Science, Kanazawa; Diabetes Center (J.M., Y.U., Y.I.), Tokyo Women’s Medical University School of Medicine, Tokyo; Department of Biochemistry (H. Yonekura), Kanazawa Medical University, Kanazawa; Research Laboratory (H.T., H.M., K.O.), Daiichi Fine Chemical Co Ltd, Takaoka; Department of Metabolism, Endocrinology, and Molecular Medicine (H.K.), Osaka City University Graduate School of Medicine, Osaka, Japan.
In response:
Yamagishi and Imaizumi speculate that kinetics and role of circulating total soluble form of receptor for advanced glycation endproducts (soluble receptor for AGE, sRAGE) may be different from those of endogenous secretory RAGE (esRAGE) in diabetes. They also suggest an alternative interpretation that serum sRAGE level may reflect tissue membrane form of RAGE expression.
Currently, 2 different types of sandwich enzyme-linked immunosorbent assays (ELISAs) are commercially available and used for measurement of circulating soluble RAGE proteins: [1] esRAGE ELISA from B-Bridge Int. esRAGE is a splice variant form of RAGE lacking transmembrane domain and secreting into extracellular space and the circulation.1 Sakurai et al developed its specific detection system using a capture monoclonal antibody (Ab) recognizing RAGE-extracellular domain and a detection polyclonal Ab for the esRAGE-specific C-terminal 16 amino acid sequence.2 This ELISA system is not influenced by coexistence of AGE ligands.2 [2] sRAGE ELISA from R&D Systems, which detects heterogenous population of total sRAGE proteins including (1) esRAGE, (2) (3) cleavage forms by metalloproteinases3 of membrane-bound full-length RAGE and esRAGE, and (4) other splice variant forms of RAGE. Similar to RAGE, esRAGE protein also has the common digestion site recognized by the proteinases, yielding deletion of the C-terminal sequence characteristic to esRAGE. These 2 assay systems are, however, constituted by individual Ab and different standard proteins. Indeed, plasma esRAGE levels in healthy subjects were found to be 5-fold less than plasma sRAGE.4 To precisely compare plasma sRAGE and esRAGE level, we developed another total sRAGE ELISA system using same capture Ab and same standard esRAGE protein in combination with a new detection monoclonal Ab. Its application in combination with esRAGE ELISA revealed that plasma esRAGE level was about 2-fold less than plasma sRAGE. esRAGE and sRAGE showed a positive correlation, with the relation stronger in healthy subjects (r=0.774; Figure, A) than in type 1 diabetic patients (r=0.500; Figure, B). Thus, although plasma sRAGE level is closely associated with plasma esRAGE level, the possibility of their distinct roles in some disease conditions cannot be completely ruled out.
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Recent immunohistological study demonstrated that esRAGE was widely expressed not only in vascular endothelial cells but also in neuronal cells, thyroid follicular cells, pancreatic β cells, adrenal cells, and hepatocytes5; all of these cells could be a source of circulating esRAGE. Expression of esRAGE was also found to be colocalized with heparan sulfate proteoglycans (HSPG) in vascular walls,5 and direct physical binding was observed between heparin/heparin derivatives and esRAGE.6 Moreover, heparitinase treatment of endothelial cells increased esRAGE level in culture media and an intravenous heparin loading caused rapid increase of circulating esRAGE level in mice and human (data not shown). Therefore, we suggest endothelial surface HSPG pool esRAGE and keep a homeostasis of circulating esRAGE to AGE ligand. Our interpretation may explain the observation that circulating esRAGE level was positively associated with serum AGE.7,8 sRAGE may also interact with heparin similarly to esRAGE.
Is circulating esRAGE or sRAGE just a biomarker or playing a role in the endogenous tissue defense against AGE toxicity? Careful attention should be paid to analysis for patients mixed with and without advanced diabetic nephropathy, because circulating esRAGE level is strongly affected by renal insufficiency.7,8 The precise mechanism is still unknown. Of note, even in the higher range of plasma esRAGE level in renal insufficiency, the patients with lower esRAGE have significantly higher risk against cardiovascular mortality.7 Very recently, Koyama et al have demonstrated that low circulating esRAGE is associated with a higher risk of progression to overt nephropathy in a prospective observational cohort study with 269 type 2 diabetic patients including 190 patients with normoalbuminuria (<30 mg/g creatinine) and 79 with microalbuminuria (30 to 299 mg/g creatinine; manuscript in submission). Geroldi et al also suggested that high sRAGE might be a marker of extreme longevity in humans.9 Although these observations need to be confirmed by a prospective study with the huge numbers of subjects calculated by the power analysis, circulating esRAGE or sRAGE level could be a powerful predictor and may be involved in the pathogenesis for various RAGE-related diseases.
Acknowledgments
Disclosures
None.
References
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[Abstract/Free Full Text] - Koyama H, Shoji T, Fukumoto S, Shinohara K, Shoji T, Emoto M, Mori K, Tahara H, Ishimura E, Kakiya R, Tabata T, Yamamoto H, Nishizawa Y. Low circulating endogenous secretory receptor for AGEs (esRAGE) predicts cardiovascular mortality in patients with end-stage renal disease. Arterioscler Thromb Vasc Biol. 2007; 27: 147–153.
[Abstract/Free Full Text] - Miura J, Yamamoto Y, Osawa M, Watanabe T, Yonekura H, Uchigata Y, Yamamoto H, Iwamoto Y. Endogenous secretory receptor for advanced glycation endproducts levels are correlated with serum pentosidine and CML in patients with type 1 diabetes. Arterioscler Thromb Vasc Biol. 2007; 27: 253–254.
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