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01-03-2012 | Article

Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology

Authors: A. K. Berner, O. Brouwers, R. Pringle, I. Klaassen, L. Colhoun, C. McVicar, S. Brockbank, J. W. Curry, T. Miyata, M. Brownlee, R. O. Schlingemann, C. Schalkwijk, A. W. Stitt

Published in: Diabetologia | Issue 3/2012

Abstract

Aims/hypothesis

Methylglyoxal (MG) is an important precursor for AGEs. Normally, MG is detoxified by the glyoxalase (GLO) enzyme system (including component enzymes GLO1 and GLO2). Enhanced glycolytic metabolism in many cells during diabetes may overpower detoxification capacity and lead to AGE-related pathology. Using a transgenic rat model that overexpresses GLO1, we investigated if this enzyme can inhibit retinal AGE formation and prevent key lesions of diabetic retinopathy.

Methods

Transgenic rats were developed by overexpression of full length GLO1. Diabetes was induced in wild-type (WT) and GLO1 rats and the animals were killed after 12 or 24 weeks of hyperglycaemia. N ^ε-(Carboxyethyl)lysine (CEL), N ^ε-(carboxymethyl)lysine (CML) and MG-derived-hydroimidazalone-1 (MG-H1) were determined by immunohistochemistry and by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS). Müller glia dysfunction was determined by glial fibrillary acidic protein (GFAP) immunoreactivity and by spatial localisation of the potassium channel Kir4.1. Acellular capillaries were quantified in retinal flat mounts.

Results

GLO1 overexpression prevented CEL and MG-H1 accumulation in the diabetic retina when compared with WT diabetic counterparts (p < 0.01). Diabetes-related increases in Müller glial GFAP levels and loss of Kir4.1 at the vascular end-feet were significantly prevented by GLO1 overexpression (p < 0.05) at both 12- and 24-week time points. GLO1 diabetic animals showed fewer acellular capillaries than WT diabetic animals (p < 0.001) at 24 weeks’ diabetes.

Conclusions/interpretation

Detoxification of MG reduces AGE adduct accumulation, which, in turn, can prevent formation of key retinal neuroglial and vascular lesions as diabetes progresses. MG-derived AGEs play an important role in diabetic retinopathy.

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Stitt AW (2010) AGEs and diabetic retinopathy. Invest Ophthalmol Vis Sci 51:4867–4874PubMedCrossRef

Beisswenger PJ, Szwergold BS, Yeo KT (2001) Glycated proteins in diabetes. Clin Lab Med 21:53–78, viPubMed

Fosmark DS, Torjesen PA, Kilhovd BK et al (2006) Increased serum levels of the specific advanced glycation end product methylglyoxal-derived hydroimidazolone are associated with retinopathy in patients with type 2 diabetes mellitus. Metabolism 55:232–236PubMedCrossRef

Yamaguchi M, Nakamura N, Nakano K et al (1998) Immunochemical quantification of crossline as a fluorescent advanced glycation endproduct in erythrocyte membrane proteins from diabetic patients with or without retinopathy. Diabet Med 15:458–462PubMedCrossRef

Genuth S, Sun W, Cleary P et al (2005) Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes 54:3103–3111PubMedCrossRef

Curtis TM, Hamilton R, Yong PH et al (2011) Muller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products. Diabetologia 54:690–698PubMedCrossRef

Stitt AW, Li YM, Gardiner TA, Bucala R, Archer DB, Vlassara H (1997) Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol 150:523–531PubMed

Gardiner TA, Anderson HR, Stitt AW (2003) Inhibition of advanced glycation end-products protects against retinal capillary basement membrane expansion during long-term diabetes. J Pathol 201:328–333PubMedCrossRef

Bhatwadekar A, Glenn JV, Figarola JL et al (2008) A new advanced glycation inhibitor, LR-90, prevents experimental diabetic retinopathy in rats. Br J Ophthalmol 92:545–547PubMedCrossRef

10.

Hammes HP, Alt A, Niwa T et al (1999) Differential accumulation of advanced glycation end products in the course of diabetic retinopathy. Diabetologia 42:728–736PubMedCrossRef

11.

Hammes HP, Du X, Edelstein D et al (2003) Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 9:294–299PubMedCrossRef

12.

Rabbani N, Thornalley PJ (2010) Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome. Amino Acids. doi:10.1007/s00726-010-0783-0

13.

Kilhovd BK, Giardino I, Torjesen PA et al (2003) Increased serum levels of the specific AGE-compound methylglyoxal-derived hydroimidazolone in patients with type 2 diabetes. Metabolism 52:163–167PubMedCrossRef

14.

Thornalley PJ, Langborg A, Minhas HS (1999) Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose. Biochem J 344(Pt 1):109–116PubMedCrossRef

15.

Glomb MA, Lang G (2001) Isolation and characterization of glyoxal-arginine modifications. J Agric Food Chem 49:1493–1501PubMedCrossRef

16.

Kuhla B, Luth HJ, Haferburg D, Boeck K, Arendt T, Munch G (2005) Methylglyoxal, glyoxal, and their detoxification in Alzheimer's disease. Ann N Y Acad Sci 1043:211–216PubMedCrossRef

17.

Shinohara M, Thornalley PJ, Giardino I et al (1998) 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 101:1142–1147PubMedCrossRef

18.

Yao D, Taguchi T, Matsumura T et al (2007) High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J Biol Chem 282:31038–31045PubMedCrossRef

19.

Brouwers O, Niessen PM, Ferreira I et al (2011) Overexpression of glyoxalase-I reduces hyperglycemia-induced levels of advanced glycation end products and oxidative stress in diabetic rats. J Biol Chem 286:1374–1380PubMedCrossRef

20.

Brouwers O, Niessen PM, Haenen G et al (2010) Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress. Diabetologia 53:989–1000PubMedCrossRef

21.

Bento CF, Fernandes R, Ramalho J et al (2010) The chaperone-dependent ubiquitin ligase CHIP targets HIF-1alpha for degradation in the presence of methylglyoxal. PLoS One 5:e15062PubMedCrossRef

22.

Queisser MA, Yao D, Geisler S et al (2010) Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes 59:670–678PubMedCrossRef

23.

Karachalias N, Babaei-Jadidi R, Ahmed N, Thornalley PJ (2003) Accumulation of fructosyl-lysine and advanced glycation end products in the kidney, retina and peripheral nerve of streptozotocin-induced diabetic rats. Biochem Soc Trans 31:1423–1425PubMedCrossRef

24.

Denis U, Lecomte M, Paget C, Ruggiero D, Wiernsperger N, Lagarde M (2002) Advanced glycation end-products induce apoptosis of bovine retinal pericytes in culture: involvement of diacylglycerol/ceramide production and oxidative stress induction. Free Radic Biol Med 33:236–247PubMedCrossRef

25.

Miller AG, Smith DG, Bhat M, Nagaraj RH (2006) Glyoxalase I is critical for human retinal capillary pericyte survival under hyperglycemic conditions. J Biol Chem 281:11864–11871PubMedCrossRef

26.

Klaassen I, Hughes JM, Vogels IM, Schalkwijk CG, van Noorden CJ, Schlingemann RO (2009) Altered expression of genes related to blood–retina barrier disruption in streptozotocin-induced diabetes. Exp Eye Res 89:4–15PubMedCrossRef

27.

McVicar CM, Colhoun LM, Abrahams JL et al (2010) Differential modulation of angiogenesis by erythropoiesis-stimulating agents in a mouse model of ischaemic retinopathy. PLoS One 5:e11870PubMedCrossRef

28.

Canning P, Glenn JV, Hsu DK, Liu FT, Gardiner TA, Stitt AW (2007) Inhibition of advanced glycation and absence of galectin-3 prevent blood–retinal barrier dysfunction during short-term diabetes. Exp Diabetes Res 51837:1–10CrossRef

29.

Stitt A, Gardiner TA, Alderson NL et al (2002) The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes 51:2826–2832PubMedCrossRef

30.

Zong H, Ward M, Madden A et al (2010) Hyperglycaemia-induced pro-inflammatory responses by retinal Muller glia are regulated by the receptor for advanced glycation end-products (RAGE). Diabetologia 53:2656–2666PubMedCrossRef

31.

Pannicke T, Iandiev I, Wurm A et al (2006) Diabetes alters osmotic swelling characteristics and membrane conductance of glial cells in rat retina. Diabetes 55:633–639PubMedCrossRef

32.

Morcos M, Du X, Pfisterer F et al (2008) Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans. Aging Cell 7:260–269PubMedCrossRef

33.

Hughes JM, Kuiper EJ, Klaassen I et al (2007) Advanced glycation end products cause increased CCN family and extracellular matrix gene expression in the diabetic rodent retina. Diabetologia 50:1089–1098PubMedCrossRef

34.

Nagai R, Hayashi CM, Xia L, Takeya M, Horiuchi S (2002) Identification in human atherosclerotic lesions of GA-pyridine, a novel structure derived from glycolaldehyde-modified proteins. J Biol Chem 277:48905–48912PubMedCrossRef

35.

Obrosova IG, Fathallah L, Greene DA (2000) Early changes in lipid peroxidation and antioxidative defense in diabetic rat retina: effect of DL-alpha-lipoic acid. Eur J Pharmacol 398:139–146PubMedCrossRef

36.

Aguilera J, Prieto JA (2001) The Saccharomyces cerevisiae aldose reductase is implied in the metabolism of methylglyoxal in response to stress conditions. Curr Genet 39:273–283PubMedCrossRef

37.

Vander Jagt DL, Hassebrook RK, Hunsaker LA, Brown WM, Royer RE (2001) 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 130–132:549–562PubMedCrossRef

38.

Padival S, Nagaraj RH (2006) Pyridoxamine inhibits maillard reactions in diabetic rat lenses. Ophthalmic Res 38:294–302PubMedCrossRef

39.

Payet O, Maurin L, Bonne C, Muller A (2004) Hypoxia stimulates glutamate uptake in whole rat retinal cells in vitro. Neurosci Lett 356:148–150PubMedCrossRef

40.

Hammes HP, Federoff HJ, Brownlee M (1995) Nerve growth factor prevents both neuroretinal programmed cell death and capillary pathology in experimental diabetes. Mol Med 1:527–534PubMed

41.

Mizutani M, Gerhardinger C, Lorenzi M (1998) Muller cell changes in human diabetic retinopathy. Diabetes 47:445–449PubMedCrossRef

42.

Fischer AJ, Scott MA, Ritchey ER, Sherwood P (2009) Mitogen-activated protein kinase-signaling regulates the ability of Muller glia to proliferate and protect retinal neurons against excitotoxicity. Glia 57:1538–1552PubMedCrossRef

43.

Shelton MD, Kern TS, Mieyal JJ (2007) Glutaredoxin regulates nuclear factor kappa-B and intercellular adhesion molecule in Muller cells: model of diabetic retinopathy. J Biol Chem 282:12467–12474PubMedCrossRef

44.

Winkler BS, Starnes CA, Sauer MW, Firouzgan Z, Chen SC (2004) Cultured retinal neuronal cells and Muller cells both show net production of lactate. Neurochem Int 45:311–320PubMedCrossRef

45.

Reichenbach A, Wurm A, Pannicke T, Iandiev I, Wiedemann P, Bringmann A (2007) Muller cells as players in retinal degeneration and edema. Graefes Arch Clin Exp Ophthalmol 245:627–636PubMedCrossRef

46.

Connors NC, Adams ME, Froehner SC, Kofuji P (2004) The potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex via alpha-syntrophin in glia. J Biol Chem 279:28387–28392PubMedCrossRef

47.

Miller AG, Tan G, Binger KJ et al (2010) Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function. Diabetes 59:3208–3215PubMedCrossRef

Title: Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology
Authors: A. K. Berner
O. Brouwers
R. Pringle
I. Klaassen
L. Colhoun
C. McVicar
S. Brockbank
J. W. Curry
T. Miyata
M. Brownlee
R. O. Schlingemann
C. Schalkwijk
A. W. Stitt
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: Diabetologia / Issue 3/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-011-2393-0

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