doi: 10.1161/ATVBAHA.107.139923
© 2007 American Heart Association, Inc.
Letters to the Editor |
Serum Levels of Soluble Form of Receptor for Advanced Glycation End Products (sRAGE) May Reflect Tissue RAGE Expression In Diabetes
Department of Medicine, Kurume University School of Medicine, Kurume, Japan
To the Editor:
I have read two interesting papers about endogenous C-truncated splice isoform of secretory receptor for advanced glycation end products (esRAGE), which were recently published in your journal.1,2 The findings that esRAGE levels are correlated with serum pentosidine and carboxymethyllysine in type 1 diabetes by Miura et al1 are consistent with our and Tan’s previous observations that serum levels of total soluble form of RAGE (sRAGE) were positively, but not inversely, correlated with circulating AGE levels in nondiabetic and type 2 diabetic subjects, respectively.3,4 These observations suggest that endogenous esRAGE or sRAGE levels are not sufficient to eliminate circulating AGEs efficiently in vivo. However, Koyama et al2,5 recently reported in ATVB that decreased levels of esRAGE were associated with comorbidity including the metabolic syndrome and atherosclerosis and with cardiovascular mortality in end-stage renal disease patients. Therefore, it is unlikely that esRAGE protects against these devastating disorders by working as a decoy receptor for AGEs in vivo. Indeed, they also claimed in their article that pentosidine level was positively, but not inversely, associated with esRAGE.
In contrast to the case of esRAGE, circulating sRAGE levels are increased, rather than decreased, in both type 1 and type 2 diabetic patients.4,6,7 Further, the following evidence supports the concept that circulating sRAGE may be elevated in response to serum AGE levels and reflect tissue RAGE expression in diabetes, thereby acting as a negative feedback agent against the AGE-elicited vascular injury: (1) RAGE belongs to the same immunoglobulin superfamily as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and that serum levels of soluble forms of ICAM-1 and VCAM-1 are elevated in patients with diabetes by reflecting upregulation of these adhesion molecules in endothelial cells (ECs).8 (2) Angiotensin II increases RAGE mRNA levels in ECs and subsequently stimulates sRAGE formation in vitro. Treatment with telmisartan, an angiotensin II type 1 receptor blocker, not only inhibits the angiotensin II-elicited sRAGE generation by ECs, but also decreases serum levels of sRAGE in patients with essential hypertension.9 (3) AGEs are positive regulators of cell expression of RAGE and that RAGE is upregulated in atherosclerotic plaques in diabetes, diabetic nephropathy, and retinopathy.10–12 (4) Vitreous levels of sRAGE are increased in proliferative retinal diseases by reflecting enhanced RAGE expression in epiretinal membranes of the eyes.12 Moreover, sRAGE levels are positively associated with the presence of coronary artery disease in type 2 diabetes.7 In addition, we have very recently found that serum levels of sRAGE are positively correlated with inflammatory biomarkers such as tumor necrosis factor-alpha (TNF-
) and monocyte chemoattractant protein-1 (MCP-1) in type 2 diabetic patients. Taken together, these observations suggest that the kinetics and role of sRAGE and esRAGE in diabetes could differ and that sRAGE level may become a novel biomarker of vascular injury in patients with type 2 diabetes.
Acknowledgments
Disclosures
None.
References
1. 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.
2. 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 predicts cardiovascular mortality in patients with end-stage renal disease. Arterioscler Thromb Vasc Biol. 2007; 27: 147–153.
3. Yamagishi S, Adachi H, Nakamura K, Matsui T, Jinnouchi Y, Takenaka K, Takeuchi M, Enomoto M, Furuki K, Hino A, Shigeto Y, Imaizumi T. Positive association between serum levels of advanced glycation end products and the soluble form of receptor for advanced glycation end products in nondiabetic subjects. Metabolism. 2006; 55: 1227–1231.[CrossRef][Medline] [Order article via Infotrieve]
4. Tan KC, Shiu SW, Chow WS, Leng L, Bucala R, Betteridge DJ. Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes. Diabetologia. 2006; 49: 2756–2762.[CrossRef][Medline] [Order article via Infotrieve]
5. Koyama H, Shoji T, Yokoyama H, Motoyama K, Mori K, Fukumoto S, Emoto M, Shoji T, Tamei H, Matsuki H, Sakurai S, Yamamoto Y, Yonekura H, Watanabe T, Yamamoto H, Nishizawa Y. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Arterioscler Thromb Vasc Biol. 2005; 25: 2587–2593.
6. Challier M, Jacqueminet S, Benabdesselam O, grimaldi A, Beaudeux JL. Increased serum concentrations of soluble receptor for advanced glycation endproducts in patients with type 1 diabetes. Clin Chem. 2005; 51: 1749–1750.
7. Nakamura K, Sho-ichi Yamagishi, Hisashi Adachi, Yayoi Kurita-Nakamura, Takanori Matsui, Takafumi Yoshida, Akira Sato, and Tsutomu Imaizumi. Elevation of soluble form of receptor for advanced glycation end products (sRAGE) in diabetic subjects with coronary artery disease. Diabetes Metab Res Rev. 2006;10.1002/dmrr. 690.
8. Steiner M, Reinhardt KM, Krammer B, Ernst B, Blann AD. Increased levels of soluble adhesion molecules in type 2 (non-insulin dependent) diabetes mellitus are independent of glycaemic control. Thromb Haemost. 1994; 72: 979–984.[Medline] [Order article via Infotrieve]
9. Nakamura K, Yamagishi S, Nakamura Y, Takenaka K, Matsui T, Jinnouchi Y, Imaizumi T. Telmisartan inhibits expression of a receptor for advanced glycation end products (RAGE) in angiotensin-II-exposed endothelial cells and decreases serum levels of soluble RAGE in patients with essential hypertension. Microvasc Res. 2005; 70: 137–141.[CrossRef][Medline] [Order article via Infotrieve]
10. Cipollone F, Iezzi A, Fazia M, Zucchelli M, Pini B, Cuccurullo C, De Cesare D, De Blasis G, Muraro R, Bei R, Chiarelli F, Schmidt AM, Cuccurullo F, Mezzetti A. The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Circulation. 2003; 108: 1070–1077.
11. Tanji N, Markowitz GS, Fu C, Kislinger T, Taguchi A, Pischetsrieder M, Stern D, Schmidt AM, D’Agati VD. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J Am Soc Nephrol. 2000; 11: 1656–1666.
12. Pachydaki SI, Tari SR, Lee SE, Ma W, Tseng JJ, Sosunov AA, Cataldergirmen G, Scarmeas N, Caspersen C, Chang S, Schiff WM, Schmidt AM, Barile GR. Upregulation of RAGE and its ligands in proliferative retinal disease. Exp Eye Res. 2006; 82: 807–815.[CrossRef][Medline] [Order article via Infotrieve]
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