Skip to main content
SpringerLink
Log in

High serum level of methylglyoxal-derived AGE, Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine, independently relates to renal dysfunction

  • Original article
  • Published:
Clinical and Experimental Nephrology Aims and scope Submit manuscript

Abstract

Background

The dicarbonyl methylglyoxal reacts primarily with arginine residues to form advanced glycation end products, including Nδ-(5-hydro-5-methyl-4 -imidazolone-2-yl)-ornithine (MG-H1), which are risk factors for not only diabetic complications but also lifestyle-related disease including renal dysfunction. However, the data on serum level and clinical significance of this substance in chronic kidney disease are limited.

Methods

Serum levels of MG-H1 and Nε-(carboxymethyl) lysine (CML) in 50 patients with renal dysfunction were measured by liquid chromatography/triple-quadruple mass spectrometry.

Results

The median serum MG-H1 levels in patients with estimated glomerular filtration rate (eGFR) of ≥30, 15–30, and <15 ml/min/1.73 m2 was 4.16, 12.58, and 14.66 mmol/mol Lys, respectively (p > 0.05). On the other hand, MG-H1 levels in patients with HbA1c of <6 and ≥6 % was 12.85 and 10.45 mmol/mol Lys, respectively, the difference between which is not significant. In logistic regression analysis, decreased renal function (eGFR <15 ml/min/1.73 m2) significantly associated with high serum levels of MG-H1 [odds ratio: 9.39 (95 % confidence interval 1.528–57.76), p = 0.015; Spearman rank correlation: MG-H1 vs. eGFR, r = −0.691, p < 0.01]. In contrast, the serum level of CML did not correlate with eGFR, but correlated with systolic blood pressure [odds ratio 16.17 (95 % confidence interval 1.973–132.5), p = 0.010; Spearman rank correlation coefficient: CML vs. eGFR, r = 0.454, p < 0.01].

Conclusion

These results showed that the serum concentration of MG-H1 was strongly related to renal function rather than to DM.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20.

    Article  CAS  PubMed  Google Scholar 

  2. Peppa M, Uribarri J, Vlassara H. The role of advanced glycation end products in the development of atherosclerosis. Curr Diabetes Rep. 2004;4(1):31–6.

    Article  Google Scholar 

  3. Thornalley PJ, Langborg A, Minhas HS. Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J. 1999;344(Pt 1):109–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nagai R, Unno Y, Hayashi MC, Masuda S, Hayase F, Kinae N et al. Peroxynitrite induces formation of N(epsilon)-(carboxymethyl) lysine by the cleavage of Amadori product and generation of glucosone and glyoxal from glucose: novel pathways for protein modification by peroxynitrite. Diabetes. 2002;51(9):2833–9.

    Article  CAS  PubMed  Google Scholar 

  5. Nagai R, Hayashi CM, Xia L, Takeya M, Horiuchi S. Identification in human atherosclerotic lesions of GA-pyridine, a novel structure derived from glycolaldehyde-modified proteins. J Biol Chem. 2002;277(50):48905–12.

    Article  CAS  PubMed  Google Scholar 

  6. Brouwers O, Niessen PM, Ferreira I, Miyata T, Scheffer PG, Teerlink T et al. Overexpression of glyoxalase-I reduces hyperglycemia-induced levels of advanced glycation end products and oxidative stress in diabetic rats. J Biol Chem. 2011;286(2):1374–80. doi:10.1074/jbc.M110.144097.

    Article  CAS  PubMed  Google Scholar 

  7. Makino H, Shikata K, Hironaka K, Kushiro M, Yamasaki Y, Sugimoto H et al. Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephropathy. Kidney Int. 1995;48(2):517–26.

    Article  CAS  PubMed  Google Scholar 

  8. Matafome P, Sena C, Seica R. Methylglyoxal, obesity, and diabetes. Endocrine. 2013;43(3):472–84. doi:10.1007/s12020-012-9795-8.

    Article  CAS  PubMed  Google Scholar 

  9. Hanssen NM, Stehouwer CD, Schalkwijk CG. Methylglyoxal and glyoxalase I in atherosclerosis. Biochem Soc Trans. 2014;42(2):443–9. doi:10.1042/BST20140001.

    Article  CAS  PubMed  Google Scholar 

  10. Srikanth V, Westcott B, Forbes J, Phan TG, Beare R, Venn A et al. Methylglyoxal, cognitive function and cerebral atrophy in older people. J Gerontol A Biol Sci Med Sci. 2013;68(1):68–73. doi:10.1093/gerona/gls100.

    Article  Google Scholar 

  11. Lu J, Randell E, Han Y, Adeli K, Krahn J, Meng QH. Increased plasma methylglyoxal level, inflammation, and vascular endothelial dysfunction in diabetic nephropathy. Clin Biochem. 2011;44(4):307–11. doi:10.1016/j.clinbiochem.2010.11.004.

    Article  CAS  PubMed  Google Scholar 

  12. Oya T, Hattori N, Mizuno Y, Miyata S, Maeda S, Osawa T et al. Methylglyoxal modification of protein. Chemical and immunochemical characterization of methylglyoxal-arginine adducts. J Biol Chem. 1999;274(26):18492–502.

    Article  CAS  PubMed  Google Scholar 

  13. Ahmed N, Thornalley PJ, Dawczynski J, Franke S, Strobel J, Stein G et al. Methylglyoxal-derived hydroimidazolone advanced glycation end-products of human lens proteins. Invest Ophthalmol Vis Sci. 2003;44(12):5287–92.

    Article  Google Scholar 

  14. Beisswenger PJ, Howell SK, Russell GB, Miller ME, Rich SS, Mauer M. Early progression of diabetic nephropathy correlates with methylglyoxal-derived advanced glycation end products. Diabetes Care. 2013;36(10):3234–9. doi:10.2337/dc12-2689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Randell EW, Vasdev S, Gill V. Measurement of methylglyoxal in rat tissues by electrospray ionization mass spectrometry and liquid chromatography. J Pharmacol Toxicol Methods. 2005;51(2):153–7.

    Article  CAS  PubMed  Google Scholar 

  16. Seino Y, Nanjo K, Tajima N, Kadowaki T, Kashiwagi A, Araki E et al. Report of the committee on the classification and diagnostic criteria of diabetes mellitus. J Diabetes Investig. 2010;1(5):212–28. doi:10.1111/j.2040-1124.2010.00074.x.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53(6):982–92. doi:10.1053/j.ajkd.2008.12.034.

    Article  CAS  PubMed  Google Scholar 

  18. Jo-Watanabe A, Ohse T, Nishimatsu H, Takahashi M, Ikeda Y, Wada T et al. Glyoxalase I reduces glycative and oxidative stress and prevents age-related endothelial dysfunction through modulation of endothelial nitric oxide synthase phosphorylation. Aging Cell. 2014;13(3):519–28. doi:10.1111/acel.12204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nakano M, Kubota M, Owada S, Nagai R. The pentosidine concentration in human blood specimens is affected by heating. Amino Acids. 2013;44:1451–6. doi:10.1007/s00726-011-1180-z.

    Article  CAS  PubMed  Google Scholar 

  20. Frizzell N, Rajesh M, Jepson MJ, Nagai R, Carson JA, Thorpe SR et al. Succination of thiol groups in adipose tissue proteins in diabetes: succination inhibits polymerization and secretion of adiponectin. J Biol Chem. 2009;284(38):25772–81. doi:10.1074/jbc.M109.019257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. McLellan AC, Thornalley PJ, Benn J, Sonksen PH. Glyoxalase system in clinical diabetes mellitus and correlation with diabetic complications. Clinical Sci (Lond). 1994;87(1):21–9.

    Article  CAS  Google Scholar 

  22. Scheijen JL, Schalkwijk CG. Quantification of glyoxal, methylglyoxal and 3-deoxyglucosone in blood and plasma by ultra performance liquid chromatography tandem mass spectrometry: evaluation of blood specimen. Clin Chem Lab Med CCLM/FESCC. 2014;52(1):85–91. doi:10.1515/cclm-2012-0878.

    CAS  Google Scholar 

  23. Genuth S, Sun W, Cleary P, Gao X, Sell DR, Lachin J et al. Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes. Diabetes. 2015;64(1):266–78. doi:10.2337/db14-0215.

    Article  CAS  PubMed  Google Scholar 

  24. Dworacka M, Winiarska H, Szymanska M, Szczawinska K, Wierusz-Wysocka B. Serum N-epsilon-(carboxymethyl)lysine is elevated in nondiabetic coronary heart disease patients. J Basic Clin Physiol Pharmacol. 2002;13(3):201–13.

    Article  CAS  PubMed  Google Scholar 

  25. Inoue R, Sakata N, Nakai K, Aikawa H, Tsutsumi M, Nii K et al. Nepsilon-(Carboxymethyl)lysine in debris from carotid artery stenting: multiple versus nonmultiple postoperative lesions. J Stroke Cerebrovasc Dis. 2014;23(10):2827–33. doi:10.1016/j.jstrokecerebrovasdis.2014.07.002.

    Article  PubMed  Google Scholar 

  26. Sakata N, Takeuchi K, Noda K, Saku K, Tachikawa Y, Tashiro T et al. Calcification of the medial layer of the internal thoracic artery in diabetic patients: relevance of glycoxidation. J Vasc Res. 2003;40(6):567–74.

    Article  CAS  PubMed  Google Scholar 

  27. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058–70. doi:10.1161/CIRCRESAHA.110.223545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lapolla A, Piarulli F, Sartore G, Ceriello A, Ragazzi E, Reitano R et al. Advanced glycation end products and antioxidant status in type 2 diabetic patients with and without peripheral artery disease. Diabetes Care. 2007:30(3):670–6.

    Article  CAS  PubMed  Google Scholar 

  29. Rabbani N, Thornalley PJ. Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids. 2012;42(4):1133–42. doi:10.1007/s00726-010-0783-0.

    Article  CAS  PubMed  Google Scholar 

  30. Lapolla A, Flamini R, Lupo A, Arico NC, Rugiu C, Reitano R et al. Evaluation of glyoxal and methylglyoxal levels in uremic patients under peritoneal dialysis. Ann N Y Acad Sci. 2005;1043:217–24.

    Article  CAS  PubMed  Google Scholar 

  31. Shiu SW, Tan KC, Wong Y, Leng L, Bucala R. Glycoxidized LDL increases lectin-like oxidized low density lipoprotein receptor-1 in diabetes mellitus. Atherosclerosis. 2009;203(2):522–7. doi:10.1016/j.atherosclerosis.2008.07.012.

    Article  CAS  PubMed  Google Scholar 

  32. Hanssen NM, Wouters K, Huijberts MS, Gijbels MJ, Sluimer JC, Scheijen JL et al. Higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques are associated with a rupture-prone phenotype. Eur Heart J. 2014;35(17):1137–46. doi:10.1093/eurheartj/eht402.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Nephrology and Rheumatology, Faculty of Medicine, Fukuoka University, 7-45-1, Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Kenji Ito, Maho Watanabe, Ayako Mimata, Yasuhiro Abe, Tetsuhiko Yasuno, Yoshie Sasatomi, Katsuhisa Miyake, Naoko Ueki, Aki Hamauchi & Hitoshi Nakashima

  2. Division of Pathology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan

    Noriyuki Sakata

  3. Laboratory of Food and Regulation Biology Department of Bioscience, School of Agriculture, Tokai University, Kumamoto, Japan

    Ryoji Nagai & Jun-ichi Shirakawa

Authors
  1. Kenji Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noriyuki Sakata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ryoji Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jun-ichi Shirakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maho Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ayako Mimata
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasuhiro Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tetsuhiko Yasuno
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshie Sasatomi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Katsuhisa Miyake
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Naoko Ueki
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Aki Hamauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hitoshi Nakashima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kenji Ito.

Ethics declarations

Conflict of interest

None.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ito, K., Sakata, N., Nagai, R. et al. High serum level of methylglyoxal-derived AGE, Nδ-(5-hydro-5-methyl-4-imidazolone-2-yl)-ornithine, independently relates to renal dysfunction. Clin Exp Nephrol 21, 398–406 (2017). https://doi.org/10.1007/s10157-016-1301-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10157-016-1301-9

Keywords

Search

Navigation