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01.01.2014 | Article

Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes

verfasst von: Olaf Brouwers, Petra M. G. Niessen, Toshio Miyata, Jakob A. Østergaard, Allan Flyvbjerg, Carine J. Peutz-Kootstra, Jonas Sieber, Peter H. Mundel, Michael Brownlee, Ben J. A. Janssen, Jo G. R. De Mey, Coen D. A. Stehouwer, Casper G. Schalkwijk

Erschienen in: Diabetologia | Ausgabe 1/2014

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Abstract

Aims/hypothesis

In diabetes, advanced glycation end-products (AGEs) and the AGE precursor methylglyoxal (MGO) are associated with endothelial dysfunction and the development of microvascular complications. In this study we used a rat model of diabetes, in which rats transgenically overexpressed the MGO-detoxifying enzyme glyoxalase-I (GLO-I), to determine the impact of intracellular glycation on vascular function and the development of early renal changes in diabetes.

Methods

Wild-type and Glo1-overexpressing rats were rendered diabetic for a period of 24 weeks by intravenous injection of streptozotocin. Mesenteric arteries were isolated to study ex vivo vascular reactivity with a wire myograph and kidneys were processed for histological examination. Glycation was determined by mass spectrometry and immunohistochemistry. Markers for inflammation, endothelium dysfunction and renal dysfunction were measured with ELISA-based techniques.

Results

Diabetes-induced formation of AGEs in mesenteric arteries and endothelial dysfunction were reduced by Glo1 overexpression. Despite the absence of advanced nephrotic lesions, early markers of renal dysfunction (i.e. increased glomerular volume, decreased podocyte number and diabetes-induced elevation of urinary markers albumin, osteopontin, kidney-inflammation-molecule-1 and nephrin) were attenuated by Glo1 overexpression. In line with this, downregulation of Glo1 in cultured endothelial cells resulted in increased expression of inflammation and endothelium dysfunction markers. In fully differentiated cultured podocytes incubation with MGO resulted in apoptosis.

Conclusions/interpretation

This study shows that effective regulation of the GLO-I enzyme is important in the prevention of vascular intracellular glycation, endothelial dysfunction and early renal impairment in experimental diabetes. Modulating the GLO-I pathway therefore may provide a novel approach to prevent vascular complications in diabetes.

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Skyler JS, Bergenstal R, Bonow RO et al (2009) Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Circulation 119:351–357PubMedCrossRef

Clark CM Jr, Lee DA (1995) Prevention and treatment of the complications of diabetes mellitus. N Engl J Med 332:1210–1217PubMedCrossRef

Klein R (1995) Hyperglycemia and microvascular and macrovascular disease in diabetes. Diabetes Care 18:258–268PubMedCrossRef

Cines DB, Pollak ES, Buck CA et al (1998) Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 91:3527–3561PubMed

Brownlee M (2001) Biochemistry and molecular cell biology of diabetic complications. Nature 414:813–820PubMedCrossRef

Monnier VM, Cerami A (1981) Nonenzymatic browning in vivo: possible process for aging of long-lived proteins. Science 211:491–493PubMedCrossRef

Brownlee M (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54:1615–1625PubMedCrossRef

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

Thornalley PJ (1993) The glyoxalase system in health and disease. Mol Aspects Med 14:287–371PubMedCrossRef

10.

Rosca MG, Mustata TG, Kinter MT et al (2005) Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. Am J Physiol Renal Physiol 289:F420–F430PubMedCrossRef

11.

Beisswenger PJ, Drummond KS, Nelson RG, Howell SK, Szwergold BS, Mauer M (2005) Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress. Diabetes 54:3274–3281PubMedCrossRef

12.

Ogawa S, Nakayama K, Nakayama M et al (2010) Methylglyoxal is a predictor in type 2 diabetic patients of intima-media thickening and elevation of blood pressure. Hypertension 56:471–476PubMedCrossRef

13.

Brouwers O, Niessen PM, Ferreira I et al (2011) Overexpression of glyoxalase-I reduces hyperglycemia-induced levels of advanced glycation endproducts and oxidative stress in diabetic rats. J Biol Chem 286:7CrossRef

14.

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

15.

Berner AK, Brouwers O, Pringle R et al (2012) Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology. Diabetologia 55:845–854PubMedCrossRef

16.

McLellan AC, Phillips SA, Thornalley PJ (1993) The assay of S-D-lactoylglutathione in biological systems. Biochem Soc Trans 21:164SPubMed

17.

Schalkwijk CG, Baidoshvili A, Stehouwer CD, van Hinsbergh VW, Niessen HW (2004) Increased accumulation of the glycoxidation product Nepsilon-(carboxymethyl)lysine in hearts of diabetic patients: generation and characterisation of a monoclonal anti-CML antibody. Biochim Biophys Acta 1636:82–89PubMedCrossRef

18.

Ostergaard JA, Bjerre M, RamachandraRao SP et al (2012) Mannan-binding lectin in diabetic kidney disease: the impact of mouse genetics in a type 1 diabetes model. Exp Diabetes Res 2012:678381PubMed

19.

Waterval WA, Scheijen JL, Ortmans-Ploemen MM, Habets-van der Poel CD, Bierau J (2009) Quantitative UPLC-MS/MS analysis of underivatised amino acids in body fluids is a reliable tool for the diagnosis and follow-up of patients with inborn errors of metabolism. Clin Chim Acta 407:36–42PubMedCrossRef

20.

Hanssen NM, Engelen L, Ferreira I et al (2013) Plasma levels of advanced glycation endproducts Nepsilon-(carboxymethyl)lysine, Nepsilon-(carboxyethyl)lysine, and pentosidine are not independently associated with cardiovascular disease in individuals with or without type 2 diabetes: the Hoorn and CODAM studies. J Clin Endocrinol Metab 98:E1369–1373

21.

Scheijen JL, Schalkwijk CG (2013) 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 13:1–7CrossRef

22.

Nagareddy PR, Xia Z, MacLeod KM, McNeill JH (2006) N-Acetylcysteine prevents nitrosative stress-associated depression of blood pressure and heart rate in streptozotocin diabetic rats. J Cardiovasc Pharmacol 47:513–520PubMedCrossRef

23.

Hink U, Li H, Mollnau H et al (2001) Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ Res 88:E14–E22PubMedCrossRef

24.

Dhar A, Dhar I, Desai KM, Wu L (2010) Methylglyoxal scavengers attenuate endothelial dysfunction induced by methylglyoxal and high concentrations of glucose. Br J Pharmacol 161:1843–1856PubMedCrossRef

25.

Brouwers O, Teerlink T, van Bezu J, Barto R, Stehouwer CD, Schalkwijk CG (2008) Methylglyoxal and methylglyoxal-arginine adducts do not directly inhibit endothelial nitric oxide synthase. Ann N Y Acad Sci 1126:231–234PubMedCrossRef

26.

Tailor A, Granger DN (2000) Role of adhesion molecules in vascular regulation and damage. Curr Hypertens Rep 2:78–83PubMedCrossRef

27.

Nin JW, Jorsal A, Ferreira I et al (2011) Higher plasma levels of advanced glycation end products are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study. Diabetes Care 34:442–447PubMedCrossRef

28.

Vlassara H, Fuh H, Donnelly T, Cybulsky M (1995) Advanced glycation endproducts promote adhesion molecule (VCAM-1, ICAM-1) expression and atheroma formation in normal rabbits. Mol Med 1:447–456PubMed

29.

Chang KC, Hsu KL, Tseng CD, Lin YD, Cho YL, Tseng YZ (2006) Aminoguanidine prevents arterial stiffening and cardiac hypertrophy in streptozotocin-induced diabetes in rats. Br J Pharmacol 147:944–950PubMedCrossRef

30.

Soulis T, Sastra S, Thallas V et al (1999) A novel inhibitor of advanced glycation end-product formation inhibits mesenteric vascular hypertrophy in experimental diabetes. Diabetologia 42:472–479PubMedCrossRef

31.

Hirose K, Osterby R, Nozawa M, Gundersen HJ (1982) Development of glomerular lesions in experimental long-term diabetes in the rat. Kidney Int 21:689–695PubMedCrossRef

32.

Bidani AK, Picken M, Hacioglu R, Williamson G, Griffin KA (2007) Spontaneously reduced blood pressure load in the rat streptozotocin-induced diabetes model: potential pathogenetic relevance. Am J Physiol Renal Physiol 292:F647–F654PubMedCrossRef

33.

Astrup AS, Tarnow L, Pietraszek L et al (2008) Markers of endothelial dysfunction and inflammation in type 1 diabetic patients with or without diabetic nephropathy followed for 10 years: association with mortality and decline of glomerular filtration rate. Diabetes Care 31:1170–1176PubMedCrossRef

34.

Stehouwer CD, Stroes ES, Hackeng WH, Mulder PG, Den Ottolander GJ (1991) von Willebrand factor and development of diabetic nephropathy in IDDM. Diabetes 40:971–976PubMedCrossRef

35.

Schalkwijk CG, Stehouwer CD (2005) Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 109:143–159CrossRef

36.

Ichimura T, Bonventre JV, Bailly V et al (1998) Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 273:4135–4142PubMedCrossRef

37.

Nicholas SB, Liu J, Kim J et al (2010) Critical role for osteopontin in diabetic nephropathy. Kidney Int 77:588–600PubMedCrossRef

38.

Mauer SM, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC (1984) Structural–functional relationships in diabetic nephropathy. J Clin Invest 74:1143–1155PubMedCrossRef

39.

Cooper ME (2001) Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy. Diabetologia 44:1957–1972PubMedCrossRef

40.

Dai FX, Diederich A, Skopec J, Diederich D (1993) Diabetes-induced endothelial dysfunction in streptozotocin-treated rats: role of prostaglandin endoperoxides and free radicals. J Am Soc Nephrol 4:1327–1336PubMed

41.

De Vriese AS, Van de Voorde J, Blom HJ, Vanhoutte PM, Verbeke M, Lameire NH (2000) The impaired renal vasodilator response attributed to endothelium-derived hyperpolarizing factor in streptozotocin-induced diabetic rats is restored by 5-methyltetrahydrofolate. Diabetologia 43:1116–1125PubMedCrossRef

42.

Forbes JM, Thallas V, Thomas MC et al (2003) The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes. FASEB J 17:1762–1764PubMed

43.

Soulis T, Cooper ME, Vranes D, Bucala R, Jerums G (1996) Effects of aminoguanidine in preventing experimental diabetic nephropathy are related to the duration of treatment. Kidney Int 50:627–634PubMedCrossRef

44.

Siu B, Saha J, Smoyer WE, Sullivan KA, Brosius FC 3rd (2006) Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment. BMC Nephrol 7:6PubMedCrossRef

45.

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

Titel: Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes
verfasst von: Olaf Brouwers
Petra M. G. Niessen
Toshio Miyata
Jakob A. Østergaard
Allan Flyvbjerg
Carine J. Peutz-Kootstra
Jonas Sieber
Peter H. Mundel
Michael Brownlee
Ben J. A. Janssen
Jo G. R. De Mey
Coen D. A. Stehouwer
Casper G. Schalkwijk
Publikationsdatum: 01.01.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 1/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-013-3088-5

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