title: Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Universiteitssingel 50, P.O. Box 616 (box 14), 6200 MD, Maastricht, the Netherlands, olaf.brouwers@maastrichtuniversity.nl.
authors.forename: Olaf
authors.initials: O
authors.lastname: Brouwers
authors.forename: Petra M G
authors.initials: PM
authors.lastname: Niessen
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Jakob A
authors.initials: JA
authors.lastname: Østergaard
authors.forename: Allan
authors.initials: A
authors.lastname: Flyvbjerg
authors.forename: Carine J
authors.initials: CJ
authors.lastname: Peutz-Kootstra
authors.forename: Jonas
authors.initials: J
authors.lastname: Sieber
authors.forename: Peter H
authors.initials: PH
authors.lastname: Mundel
authors.forename: Michael
authors.initials: M
authors.lastname: Brownlee
authors.forename: Ben J A
authors.initials: BJ
authors.lastname: Janssen
authors.forename: Jo G R
authors.initials: JG
authors.lastname: De Mey
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism*; D007150:Immunohistochemistry; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011765:Pyruvaldehyde / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic
chemical_list: D011765:Pyruvaldehyde; D007791:Lactoylglutathione Lyase