Article

Diabetologia

, Volume 55, Issue 3, pp 845-854

First online:

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

  • A. K. BernerAffiliated withCentre for Vision and Vascular Science, Queen’s University Belfast, Royal Victoria Hospital
  • , O. BrouwersAffiliated withDepartment of Internal Medicine, Universiteit Maastricht
  • , R. PringleAffiliated withCentre for Vision and Vascular Science, Queen’s University Belfast, Royal Victoria Hospital
  • , I. KlaassenAffiliated withDepartment of Ophthalmology, Academic Medical Center, University of Amsterdam
  • , L. ColhounAffiliated withCentre for Vision and Vascular Science, Queen’s University Belfast, Royal Victoria Hospital
  • , C. McVicarAffiliated withCentre for Vision and Vascular Science, Queen’s University Belfast, Royal Victoria Hospital
  • , S. BrockbankAffiliated withCentre for Vision and Vascular Science, Queen’s University Belfast, Royal Victoria Hospital
  • , J. W. CurryAffiliated withCentre for Vision and Vascular Science, Queen’s University Belfast, Royal Victoria Hospital
  • , T. MiyataAffiliated withUnited Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine
    • , M. BrownleeAffiliated withEinstein Diabetes Research Center, Albert Einstein College of Medicine
    • , R. O. SchlingemannAffiliated withDepartment of Ophthalmology, Academic Medical Center, University of AmsterdamDepartment of Clinical and Molecular Ophthalmogenetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW)
    • , C. SchalkwijkAffiliated withDepartment of Internal Medicine, Universiteit Maastricht
    • , A. W. StittAffiliated withCentre for Vision and Vascular Science, Queen’s University Belfast, Royal Victoria Hospital Email author 

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.

Keywords

AGEs Diabetic complications Diabetic retinopathy Glyoxalase 1 Methylglyoxal Pathogenesis Retina