title: Novel diabetic mouse models as tools for investigating diabetic retinopathy.
abstract: OBJECTIVE
  Mouse models possessing green fluorescent protein (GFP) and/or human aldose reductase (hAR) in vascular tissues have been established and crossed with naturally diabetic Akita mice to produce new diabetic mouse models.
  
  
  METHODS
  Colonies of transgenic C57BL mice expressing GFP (SMAA-GFP), hAR (SMAA-hAR) or both (SMAA-GFP-hAR) in vascular tissues expressing smooth muscle actin were established and crossbred with C57BL/6-Ins2(Akita)/J (AK) mice to produce naturally diabetic offspring AK-SMAA-GFP and AK-SMAA-GFP-hAR. Aldose reductase inhibitor AL1576 (ARI) was administered in chow. Retinal and lenticular sorbitol levels were determined by HPLC. Retinal functions were evaluated by electroretinography (ERGs). Growth factor and signaling changes were determined by Western Blots using commercially available antibodies. Retinal vasculatures were isolated from the neural retina by enzymatic digestion. Flat mounts were stained with PAS-hematoxylin and analyzed.
  
  
  RESULTS
  Akita transgenics developed DM by 8 weeks of age with blood glucose levels higher in males than females. Sorbitol levels were higher in neural retinas of AK-SMAA-GFP-hAR compared to AK-SMAA-GFP mice. AK-SMAA-GFP-hAR mice also had higher VEGF levels and reduced ERG scotopic b-wave function, both of which were normalized by AL1576. AK-SMAA-GFP-hAR mice showed induction of the retinal growth factors bFGF, IGF-1, and TGFβ, as well as signaling changes in P-Akt, P-SAPK/JNK and P-44/42 MAPK that were also reduced by ARI treatment. Quantitative analysis of flat mounts in 18 week AK-SMAA-GFP-hAR mice revealed increased loss of nuclei/capillary length and a significant increase in the percentage of acellular capillaries present which was not seen in AK-SMAA-GFP-hAR treated with ARI.
  
  
  CONCLUSIONS
  These new mouse models of early onset diabetes may be valuable tools for assessing both the role of hyperglycemia and AR in the development of retinal lesions associated with diabetic retinopathy.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. pkador@unmc.edu
authors.forename: Peter F
authors.initials: PF
authors.lastname: Kador
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Makita
authors.forename: Zifeng
authors.initials: Z
authors.lastname: Zhang
authors.forename: Changmei
authors.initials: C
authors.lastname: Guo
authors.forename: James
authors.initials: J
authors.lastname: Randazzo
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Kawada
authors.forename: Neena
authors.initials: N
authors.lastname: Haider
authors.forename: Karen
authors.initials: K
authors.lastname: Blessing
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D012160:Retina / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
chemical_list: D001786:Blood Glucose