title: Retinal not systemic oxidative and inflammatory stress correlated with VEGF expression in rodent models of insulin resistance and diabetes.
abstract: OBJECTIVE
  To correlate changes between VEGF expression with systemic and retinal oxidative stress and inflammation in rodent models of obesity induced insulin resistance and diabetes.
  
  
  METHODS
  Retinal VEGF mRNA and protein levels were assessed by RT-PCR and VEGF ELISA, respectively. Urinary 8-hydroxydeoxyguanosine (8-OHdG), blood levels of C-reactive protein (CRP), malondialdehyde (MDA), and CD11b/c positive cell ratio were used as systemic inflammatory markers. Retinal expression of Nox2, Nox4, and p47phox mRNA levels were measured as oxidative stress markers. TNF-α, inter-cellular adhesion molecule-1 (ICAM-1), IL1β, and activation of nuclear factor κB (NF-κB) were used as retinal inflammatory markers.
  
  
  RESULTS
  Retinal VEGF mRNA and protein expression increased in Zucker diabetic fatty (ZDF(fa/fa)) rats and streptozotosin (STZ) induced diabetic Sprague-Dawley rats, after two months of disease, but not in Zucker fatty (ZF) rats. Systemic markers of oxidative stress and inflammation were elevated in insulin resistant and diabetic rats. Some oxidative stress and inflammatory markers (TNF-α, IL-6, ICAM-1, and IL1-β) were upregulated in the retina of ZDF(fa/fa) and STZ diabetic rats after 4 months of disease. In contrast, activation of NF-κB in the retina was observed in high fat fed nondiabetic and diabetic cis-NF-κB(EGFP) mice, ZF, ZDF(fa/fa), and STZ-induced diabetic rats.
  
  
  CONCLUSIONS
  Only persistent hyperglycemia and diabetes increased retinal VEGF expression. Some markers of inflammation and oxidative stress were elevated in the retina and systemic circulation of obese and insulin resistant rodents with and without diabetes. Induction of VEGF and its associated retinal pathologies by diabetes requires chronic hyperglycemia and factors in addition to inflammation and oxidative stress.
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Mima
authors.forename: Weier
authors.initials: W
authors.lastname: Qi
authors.forename: Junko
authors.initials: J
authors.lastname: Hiraoka-Yamomoto
authors.forename: Kyoungmin
authors.initials: K
authors.lastname: Park
authors.forename: Motonobu
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Koji
authors.initials: K
authors.lastname: Mizutani
authors.forename: Edward
authors.initials: E
authors.lastname: Yu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimada
authors.forename: Jongsoon
authors.initials: J
authors.lastname: Lee
authors.forename: Steven E
authors.initials: SE
authors.lastname: Shoelson
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
authors.forename: Christian
authors.initials: C
authors.lastname: Rask-Madsen
authors.forename: George L
authors.initials: GL
authors.lastname: King
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D012160:Retina / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D039481:CD11b Antigen; D039521:CD11c Antigen; D016328:NF-kappa B; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C467498:vascular endothelial growth factor A, rat; D008315:Malondialdehyde; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002097:C-Reactive Protein; D003849:Deoxyguanosine