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Upregulation of Glyoxalase I fails to Normalize Methylglyoxal Levels: A Possible Mechanism for Biochemical Changes in Diabetic Mouse Lenses

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Abstract

Glyoxalase I is the first enzyme in a two-enzyme glyoxalase system that metabolizes physiological methylglyoxal (MGO). MGO reacts with proteins to form irreversible adducts that may lead to crosslinking and aggregation of lens proteins in diabetes. This study examined the effect of hyperglycemia on glyoxalase I activity and its mRNA content in mouse lens epithelial cells (mLE cells) and in diabetic mouse lenses and investigated the relationship between GSH and MGO in organ cultured lenses. mLE cells cultured with 25 mM D-glucose (high glucose) showed an upregulation of glyoxalase I activity and a higher content of glyoxalase I mRNA when compared with either cells cultured with 5 mM glucose (control) or with 20 mM L-glucose + 5 mM D-glucose. MGO concentration was significantly elevated in cells cultured with high D-glucose, but not in L-glucose. GSH levels were lower in cells incubated with high glucose compared to control cells. Glyoxalase I activity and mRNA levels were elevated in diabetic lenses compared to non-diabetic control mouse lenses. MGO levels in diabetic lenses were higher than in control lenses. Incubation of lenses with buthionine sulfoximine (BSO) resulted in a dramatic decline in GSH but the MGO levels were similar to lenses incubated without BSO. Our data suggest that in mouse lenses MGO accumulation may occur independent of GSH concentration and in diabetes there is an upregulation of glyoxalase I, but this upregulation is inadequate to normalize MGO levels, which could lead to MGO retention and chemical modification of proteins.

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References

  1. Kyselova Z, Stefek M, Bauer V: Pharmacological prevention of diabetic cataract. J Diabetes Complications 18: 129–140, 2004

    Article  PubMed  CAS  Google Scholar 

  2. Thorpe SR, Baynes JW: Role of the Maillard reaction in diabetes mellitus and diseases of aging. Drugs Aging 9: 69–77, 1996

    PubMed  CAS  Google Scholar 

  3. Wells-Knecht KJ, Brinkmann E, Wells-Knecht MC, Litchfield JE, Ahmed MU, Reddy S, Zyzak DV, Thorpe SR, Baynes JW: New biomarkers of Maillard reaction damage to proteins. Nephrol Dial Transplant 11 Suppl 5: 41–47, 1996

    Google Scholar 

  4. Monnier VM, Sell DR, Nagaraj RH, Miyata S, Grandhee S, Odetti P, Ibrahim SA: Maillard reaction-mediated molecular damage to extracellular matrix and other tissue proteins in diabetes, aging, and uremia. Diabetes 41 Suppl 2: 36–41, 1992

    Google Scholar 

  5. Nagaraj RH, Monnier VM: Isolation and characterization of a blue fluorophore from human eye lens crystallins: in vitro formation from Maillard reaction with ascorbate and ribose. Biochim Biophys Acta 1116: 34–42, 1992

    PubMed  CAS  Google Scholar 

  6. Chellan P, Nagaraj RH: Early glycation products produce pentosidine cross-links on native proteins: Novel mechanism of pentosidine formation and propagation of glycation. J Biol Chem 276: 3895–3903, 2001

    Article  PubMed  CAS  Google Scholar 

  7. Argirov OK, Lin B, Ortwerth BJ: 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate (OP-lysine) is a newly identified advanced glycation end product in cataractous and aged human lenses. J Biol Chem 279: 6487–695, 2004

    Article  PubMed  CAS  Google Scholar 

  8. Nagaraj RH, Sell DR, Prabhakaram M, Ortwerth BJ, Monnier VM: High correlation between pentosidine protein crosslinks and pigmentation implicates ascorbate oxidation in human lens senescence and cataractogenesis. Proc Natl Acad Sci U S A 88: 10257–10261, 1991

    Article  PubMed  CAS  ADS  Google Scholar 

  9. Kumari K, Umar S, Bansal V, Sahib MK: Inhibition of diabetes-associated complications by nucleophilic compounds. Diabetes 40: 1079–1084, 1991

    PubMed  CAS  Google Scholar 

  10. Chellan P, Nagaraj RH: Protein crosslinking by the Maillard reaction: dicarbonyl-derived imidazolium crosslinks in aging and diabetes. Arch Biochem Biophys 368: 98–104, 1999

    Article  PubMed  CAS  Google Scholar 

  11. Sady C, Jiang CL, Chellan P, Madhun Z, Duve Y, Glomb MA, Nagaraj RH: Maillard reactions by alpha-oxoaldehydes: detection of glyoxal-modified proteins. Biochim Biophys Acta 1481: 255–264, 2000

    PubMed  CAS  Google Scholar 

  12. Thornalley PJ: Dicarbonyl intermediates in the Maillard reaction. Ann N Y Acad Sci 1043: 111–117, 2005

    Article  PubMed  CAS  ADS  Google Scholar 

  13. Shamsi FA, Nagaraj RH: Immunochemical detection of dicarbonyl-derived imidazolium protein crosslinks in human lenses. Curr Eye Res 19: 276–284, 1999

    Article  PubMed  CAS  Google Scholar 

  14. Frye EB, Degenhardt TP, Thorpe SR, Baynes JW: Role of the Maillard reaction in aging of tissue proteins. Advanced glycation end product-dependent increase in imidazolium cross-links in human lens proteins. J Biol Chem 273: 18714–18719, 1998

    Article  PubMed  CAS  Google Scholar 

  15. Thornalley PJ: Glutathione-dependent detoxification of alpha-oxoaldehydes by the glyoxalase system: involvement in disease mechanisms and antiproliferative activity of glyoxalase I inhibitors. Chem Biol Interact 111–112: 137–151, 1998

    Article  PubMed  Google Scholar 

  16. Vander Jagt DL, Hassebrook RK, Hunsaker LA, Brown WM, Royer RE: Metabolism of the 2-oxoaldehyde methylglyoxal by aldose reductase and by glyoxalase-I: roles for glutathione in both enzymes and implications for diabetic complications. Chem Biol Interact 130–132: 549–562, 2001

    Article  Google Scholar 

  17. Shamsi FA, Sharkey E, Creighton D, Nagaraj RH: Maillard reactions in lens proteins: methylglyoxal-mediated modifications in the rat lens. Exp Eye Res 70: 369–380, 2000

    Article  PubMed  CAS  Google Scholar 

  18. Shinohara M, Thornalley PJ, Giardino I, Beisswenger P, Thorpe SR, Onorato J, Brownlee M: Overexpression of glyoxalase-I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycemia-induced increases in macromolecular endocytosis. J Clin Invest 101: 1142–1147, 1998

    Article  PubMed  CAS  Google Scholar 

  19. Espinosa-Mansilla A, Duran-Meras I, Salinas F: High-performance liquid chromatographic-fluorometric determination of glyoxal, methylglyoxal, and diacetyl in urine by prederivatization to pteridinic rings. Anal Biochem 255: 263–273, 1998

    Article  PubMed  CAS  Google Scholar 

  20. Cui XL, Lou MF: The effect and recovery of long-term H2O2 exposure on lens morphology and biochemistry. Exp Eye Res 57: 157–167, 1993

    Article  PubMed  CAS  Google Scholar 

  21. Robinson ML, Overbeek PA: Differential expression of alpha A- and alpha B-crystallin during murine ocular development. Invest Ophthalmol Vis Sci 37: 2276–2284, 1996

    PubMed  CAS  Google Scholar 

  22. Obrosova IG, Stevens MJ: Effect of dietary taurine supplementation on GSH and NAD(P)-redox status, lipid peroxidation, and energy metabolism in diabetic precataractous lens. Invest Ophthalmol Vis Sci 40: 680–688, 1999

    PubMed  CAS  Google Scholar 

  23. Hegde KR, Henein MG, Varma SD: Establishment of mouse as an animal model for study of diabetic cataracts: biochemical studies. Diabetes Obes Metab 5: 113–119, 2003

    Article  PubMed  CAS  Google Scholar 

  24. Ratliff DM, Vander Jagt DJ, Eaton RP, Vander Jagt DL: Increased levels of methylglyoxal-metabolizing enzymes in mononuclear and polymorphonuclear cells from insulin-dependent diabetic patients with diabetic complications: aldose reductase, glyoxalase I, and glyoxalase II—a clinical research center study. J Clin Endocrinol Metab 81: 488–492, 1996

    Article  PubMed  CAS  Google Scholar 

  25. Thornalley PJ, Hooper NI, Jennings PE, Florkowski CM, Jones AF, Lunec J, Barnett AH: The human red blood cell glyoxalase system in diabetes mellitus. Diabetes Res Clin Pract 7: 115–120, 1989

    Article  PubMed  CAS  Google Scholar 

  26. Haik GM, Jr., Lo TW, Thornalley PJ: Methylglyoxal concentration and glyoxalase activities in the human lens. Exp Eye Res 59: 497–500, 1994

    Article  PubMed  CAS  Google Scholar 

  27. Phillips SA, Mirrlees D, Thornalley PJ: Modification of the glyoxalase system in streptozotocin-induced diabetic rats. Effect of the aldose reductase inhibitor Statil. Biochem Pharmacol 46: 805–811, 1993

    Article  PubMed  CAS  Google Scholar 

  28. Wen Y, Bekhor I: Levels of expression of hexokinase, aldose reductase and sorbitol dehydrogenase genes in lens of mouse and rat. Curr Eye Res 12: 323–332, 1993

    PubMed  CAS  Google Scholar 

  29. Kinoshita JH, Fukushi S, Kador P, Merola LO: Aldose reductase in diabetic complications of the eye. Metabolism 28: 462–469, 1979

    Article  PubMed  CAS  Google Scholar 

  30. Hegde KR, Varma SD: Cataracts in experimentally diabetic mouse: morphological and apoptotic changes. Diabetes Obes Metab 7: 200–204, 2005

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Ophthalmology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Magdalena M. Staniszewska & Ram H. Nagaraj

  2. Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA

    Ram H. Nagaraj

  3. Department of Ophthalmology, Case Western Reserve University, Wearn Bldg., Room 653, Cleveland, OH, 44106-5068, USA

    Ram H. Nagaraj

Authors
  1. Magdalena M. Staniszewska
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  2. Ram H. Nagaraj
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Correspondence to Ram H. Nagaraj.

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Staniszewska, M.M., Nagaraj, R.H. Upregulation of Glyoxalase I fails to Normalize Methylglyoxal Levels: A Possible Mechanism for Biochemical Changes in Diabetic Mouse Lenses. Mol Cell Biochem 288, 29–36 (2006). https://doi.org/10.1007/s11010-005-9115-1

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  • DOI: https://doi.org/10.1007/s11010-005-9115-1

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