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Methylglyoxal induces hyperpermeability of the blood–retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases

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Abstract

Background

One of the early signs of diabetic retinopathy is the alteration of the blood–retinal barrier (BRB), which may involve the breakdown of endothelial cell tight junctions. Methylglyoxal (MGO) is a cytotoxic metabolite that is produced from glycolysis in vivo. Elevated levels of MGO are observed in a number of pathological conditions, including neurodegenerative disorders and diabetic complications. Herein, we hypothesize that increased levels of MGO disrupt the tight junction protein known as occludin protein by matrix metalloproteinases (MMPs), leading to breakage of the BRB.

Methods

MGO was intravitreally injected into eyes of rats. BRB leakage, MMPs activity, and occludin were investigated in intravitreally MGO-injected eyes.

Results

When normoglycemic rats were intravitreally injected with 400 μM MGO, there was widespread leakage of fluorescein isothiocyanate–bovine serum albumin (FITC-BSA) from the retinal vasculature when compared to control retinas. In addition, MGO-injected retinas demonstrated increases of both activity and expression of MMP-2 and MMP-9, and the degradation of occludin was found in the MGO-injected retinas.

Conclusions

The results suggest that the activation of MMPs by elevated levels of MGO in the retina may facilitate an increase in vascular permeability by a mechanism involving proteolytic degradation of occludin. These findings may have implications for the role of MGO in the pathogenesis of diabetic retinopathy.

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References

  1. Cunha-Vaz J, Bernardes R (2005) Nonproliferative retinopathy in diabetes type 2. Initial stages and characterization of phenotypes. Prog Retin Eye Res 24:355–377

    Article  PubMed  Google Scholar 

  2. Roy S, Sato T, Paryani G, Kao R (2003) Downregulation of fibronectin overexpression reduces basement membrane thickening and vascular lesions in retinas of galactose-fed rats. Diabetes 52:1229–1234

    Article  PubMed  CAS  Google Scholar 

  3. Sander B, Larsen M, Engler C, Lund-Andersen H, Parving HH (1994) Early changes in diabetic retinopathy: capillary loss and blood–retina barrier permeability in relation to metabolic control. Acta Ophthalmol 72:553–559

    CAS  Google Scholar 

  4. Patz A (1980) Studies on retinal neovascularization. Friedenwald Lecture. Invest Ophthalmol Vis Sci 19:1133–1138

    PubMed  CAS  Google Scholar 

  5. Giebel SJ, Menicucci G, McGuire PG, Das A (2005) Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood–retinal barrier. Lab Invest 85:597–607

    Article  PubMed  CAS  Google Scholar 

  6. Sander CS, Hamm F, Elsner P, Thiele JJ (2003) Oxidative stress in malignant melanoma and non-melanoma skin cancer. Br J Dermatol 148:913–922

    Article  PubMed  CAS  Google Scholar 

  7. Kuniyasu H, Oue N, Wakikawa A, Shigeishi H, Matsutani N, Kuraoka K, Ito R, Yokozaki H, Yasui W (2002) Expression of receptors for advanced glycation end-products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer. J Pathol 196:163–170

    Article  PubMed  CAS  Google Scholar 

  8. Stitt AW, McGoldrick C, Rice-McCaldin A, McCance DR, Glenn JV, Hsu DK, Liu FT, Thorpe SR, Gardiner TA (2005) Impaired retinal angiogenesis in diabetes: role of advanced glycation end products and galectin-3. Diabetes 54:785–794

    Article  PubMed  CAS  Google Scholar 

  9. Hirahara I, Kusano E, Yanagiba S, Miyata Y, Ando Y, Muto S, Asano Y (2006) Peritoneal injury by methylglyoxal in peritoneal dialysis. Perit Dial Int 26:380–392

    PubMed  CAS  Google Scholar 

  10. Schalkwijk CG, Posthuma N, ten Brink HJ, ter Wee PM, Teerlink T (1999) Induction of 1,2-dicarbonyl compounds, intermediates in the formation of advanced glycation end-products, during heat-sterilization of glucose-based peritoneal dialysis fluids. Perit Dial Int 19:325–333

    PubMed  CAS  Google Scholar 

  11. Bento CF, Fernandes R, Matafome P, Sena C, Seica R, Pereira P (2010) Methylglyoxal-induced imbalance in the ratio of vascular endothelial growth factor to angiopoietin 2 secreted by retinal pigment epithelial cells leads to endothelial dysfunction. Exp Physiol 95:955–970

    PubMed  CAS  Google Scholar 

  12. Berkowitz BA, Lukaszew RA, Mullins CM, Penn JS (1998) Impaired hyaloidal circulation function and uncoordinated ocular growth patterns in experimental retinopathy of prematurity. Invest Ophthalmol Vis Sci 39:391–396

    PubMed  CAS  Google Scholar 

  13. Aiello LP, Gardner TW, King GL, Blankenship G, Cavallerano JD, Ferris FL 3rd, Klein R (1998) Diabetic retinopathy. Diabetes Care 21:143–156

    PubMed  CAS  Google Scholar 

  14. Randell EW, Vasdev S, Gill V (2005) Measurement of methylglyoxal in rat tissues by electrospray ionization mass spectrometry and liquid chromatography. J Pharmacol Toxicol Methods 51:153–157

    Article  PubMed  CAS  Google Scholar 

  15. Hammes HP (2003) Pathophysiological mechanisms of diabetic angiopathy. J Diabetes Complicat 17:16–19

    Article  PubMed  Google Scholar 

  16. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9:294–299

    Article  PubMed  CAS  Google Scholar 

  17. Akhand AA, Hossain K, Mitsui H, Kato M, Miyata T, Inagi R, Du J, Takeda K, Kawamoto Y, Suzuki H, Kurokawa K, Nakashima I (2001) Glyoxal and methylglyoxal trigger distinct signals for map family kinases and caspase activation in human endothelial cells. Free Radic Biol Med 31:20–30

    Article  PubMed  CAS  Google Scholar 

  18. Fukunaga M, Miyata S, Liu BF, Miyazaki H, Hirota Y, Higo S, Hamada Y, Ueyama S, Kasuga M (2004) Methylglyoxal induces apoptosis through activation of p38 MAPK in rat Schwann cells. Biochem Biophys Res Commun 320:689–695

    Article  PubMed  CAS  Google Scholar 

  19. Huang WJ, Tung CW, Ho C, Yang JT, Chen ML, Chang PJ, Lee PH, Lin CL, Wang JY (2007) Ras activation modulates methylglyoxal-induced mesangial cell apoptosis through superoxide production. Ren Fail 29:911–921

    Article  PubMed  CAS  Google Scholar 

  20. Kim J, Son JW, Lee JA, Oh YS, Shinn SH (2004) Methylglyoxal induces apoptosis mediated by reactive oxygen species in bovine retinal pericytes. J Korean Med Sci 19:95–100

    Article  PubMed  CAS  Google Scholar 

  21. Lapolla A, Flamini R, Dalla Vedova A, Senesi A, Reitano R, Fedele D, Basso E, Seraglia R, Traldi P (2003) Glyoxal and methylglyoxal levels in diabetic patients: quantitative determination by a new GC/MS method. Clin Chem Lab Med 41:1166–1173

    Article  PubMed  CAS  Google Scholar 

  22. Lapolla A, Reitano R, Seraglia R, Sartore G, Ragazzi E, Traldi P (2005) Evaluation of advanced glycation end products and carbonyl compounds in patients with different conditions of oxidative stress. Mol Nutr Food Res 49:685–690

    Article  PubMed  CAS  Google Scholar 

  23. Chaplen FW, Fahl WE, Cameron DC (1998) Evidence of high levels of methylglyoxal in cultured Chinese hamster ovary cells. Proc Natl Acad Sci USA 95:5533–5538

    Article  PubMed  CAS  Google Scholar 

  24. Kim J, Kim OS, Kim CS, Kim NH, Kim JS (2010) Cytotoxic role of methylglyoxal in rat retinal pericytes: Involvement of a nuclear factor-kappaB and inducible nitric oxide synthase pathway. Chem Biol Interact 188:86–93

    Article  PubMed  CAS  Google Scholar 

  25. Rajagopalan S, Meng XP, Ramasamy S, Harrison DG, Galis ZS (1996) Reactive oxygen species produced by macrophage-derived foam cells regulate the activity of vascular matrix metalloproteinases in vitro. Implications for atherosclerotic plaque stability. J Clin Invest 98:2572–2579

    Article  PubMed  CAS  Google Scholar 

  26. Vincenti MP (2001) The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression. Methods Mol Biol 151:121–148

    PubMed  CAS  Google Scholar 

  27. Portik-Dobos V, Anstadt MP, Hutchinson J, Bannan M, Ergul A (2002) Evidence for a matrix metalloproteinase induction/activation system in arterial vasculature and decreased synthesis and activity in diabetes. Diabetes 51:3063–3068

    Article  PubMed  CAS  Google Scholar 

  28. Uemura S, Matsushita H, Li W, Glassford AJ, Asagami T, Lee KH, Harrison DG, Tsao PS (2001) Diabetes mellitus enhances vascular matrix metalloproteinase activity: role of oxidative stress. Circ Res 88:1291–1298

    Article  PubMed  CAS  Google Scholar 

  29. Del Prete D, Anglani F, Forino M, Ceol M, Fioretto P, Nosadini R, Baggio B, Gambaro G (1997) Down-regulation of glomerular matrix metalloproteinase-2 gene in human NIDDM. Diabetologia 40:1449–1454

    Article  PubMed  Google Scholar 

  30. Song RH, Singh AK, Leehey DJ (1999) Decreased glomerular proteinase activity in the streptozotocin diabetic rat. Am J Nephrol 19:441–446

    Article  PubMed  CAS  Google Scholar 

  31. Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J Neurosci 21:7724–7732

    PubMed  CAS  Google Scholar 

  32. Alexander JS, Elrod JW (2002) Extracellular matrix, junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation. J Anat 200:561–574

    Article  PubMed  CAS  Google Scholar 

  33. Grant MB, Caballero S, Tarnuzzer RW, Bass KE, Ljubimov AV, Spoerri PE, Galardy RE (1998) Matrix metalloproteinase expression in human retinal microvascular cells. Diabetes 47:1311–1317

    Article  PubMed  CAS  Google Scholar 

  34. Behzadian MA, Windsor LJ, Ghaly N, Liou G, Tsai NT, Caldwell RB (2003) VEGF-induced paracellular permeability in cultured endothelial cells involves urokinase and its receptor. FASEB J 17:752–754

    PubMed  CAS  Google Scholar 

  35. Moore TC, Moore JE, Kaji Y, Frizzell N, Usui T, Poulaki V, Campbell IL, Stitt AW, Gardiner TA, Archer DB, Adamis AP (2003) The role of advanced glycation end products in retinal microvascular leukostasis. Invest Ophthalmol Vis Sci 44:4457–4464

    Article  PubMed  Google Scholar 

  36. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123:1777–1788

    Article  PubMed  CAS  Google Scholar 

  37. Watson PM, Anderson JM, Vanltallie CM, Doctrow SR (1991) The tight-junction-specific protein ZO-1 is a component of the human and rat blood–brain barriers. Neurosci Lett 129:6–10

    Article  PubMed  CAS  Google Scholar 

  38. Hirase T, Staddon JM, Saitou M, Ando-Akatsuka Y, Itoh M, Furuse M, Fujimoto K, Tsukita S, Rubin LL (1997) Occludin as a possible determinant of tight junction permeability in endothelial cells. J Cell Sci 110(Pt 14):1603–1613

    PubMed  CAS  Google Scholar 

  39. Chen Y, Merzdorf C, Paul DL, Goodenough DA (1997) COOH terminus of occludin is required for tight junction barrier function in early Xenopus embryos. J Cell Biol 138:891–899

    Article  PubMed  CAS  Google Scholar 

  40. Wong V, Gumbiner BM (1997) A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J Cell Biol 136:399–409

    Article  PubMed  CAS  Google Scholar 

  41. Liu W, Hendren J, Qin XJ, Shen J, Liu KJ (2009) Normobaric hyperoxia attenuates early blood–brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. J Neurochem 108:811–820

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by a grant [K11040] from the Korea Institute of Oriental Medicine (KIOM).

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Authors and Affiliations

  1. Diabetic Complications Research Center, Division of Traditional Korean Medicine (TKM) Integrated Research, Korea Institute of Oriental Medicine, Daejeon, South Korea

    Junghyun Kim, Chan-Sik Kim, Yun Mi Lee, Kyuhyung Jo, So Dam Shin & Jin Sook Kim

  2. Diabetic Complications Research Center, Division of Traditional Korean Medicine (TKM) Integrated Research, Korea Institute of Oriental Medicine (KIOM), 1672 Yuseongdae-ro, Yuseong-gu, Daejeon, 305-811, South Korea

    Jin Sook Kim

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Kim, J., Kim, CS., Lee, Y.M. et al. Methylglyoxal induces hyperpermeability of the blood–retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases. Graefes Arch Clin Exp Ophthalmol 250, 691–697 (2012). https://doi.org/10.1007/s00417-011-1912-5

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  • DOI: https://doi.org/10.1007/s00417-011-1912-5

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