title: Methylglyoxal induces hyperpermeability of the blood-retinal barrier via the loss of tight junction proteins and the activation of matrix metalloproteinases.
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.
authors.affiliation: Diabetic Complications Research Center, Division of Traditional Korean Medicine Integrated Research, Korea Institute of Oriental Medicine, Daejeon, South Korea.
authors.forename: Junghyun
authors.initials: J
authors.lastname: Kim
authors.forename: Chan-Sik
authors.initials: CS
authors.lastname: Kim
authors.forename: Yun Mi
authors.initials: YM
authors.lastname: Lee
authors.forename: Kyuhyung
authors.initials: K
authors.lastname: Jo
authors.forename: So Dam
authors.initials: SD
authors.lastname: Shin
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D015153:Blotting, Western; D002199:Capillary Permeability / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000378:metabolism; D004789:Enzyme Activation; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D058449:Intravitreal Injections; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D062793:Occludin; D011765:Pyruvaldehyde / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012171:Retinal Vessels / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D008565:Membrane Proteins; D062793:Occludin; C568987:Ocln protein, rat; C039217:fluorescein isothiocyanate bovine serum albumin; D012710:Serum Albumin, Bovine; D011765:Pyruvaldehyde; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016650:Fluorescein-5-isothiocyanate