April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Retinal Changes in Galactose-Fed and Diabetic Mice Expressing Human Aldose Reductase and Green Fluorescent Protein in Retinal Capillary Pericytes
Author Affiliations & Notes
  • Zifeng Zhang
    Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
  • Peng Zhang
    Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
  • James Randazzo
    Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
  • Neena B. Haider
    Genetics, Cell Biology, Anatomy, Univ of Nebraska Medical Ctr, Omaha, Nebraska
  • Karen Blessing
    Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
  • Peter F. Kador
    Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska
    Ophthalmology and Visual Sciences, Uinversity of Nebraska Medical Center, Omaha, Nebraska
  • Footnotes
    Commercial Relationships  Zifeng Zhang, None; Peng Zhang, None; James Randazzo, None; Neena B. Haider, None; Karen Blessing, None; Peter F. Kador, None
  • Footnotes
    Support  NIH EY016730
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 3573. doi:https://doi.org/
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      Zifeng Zhang, Peng Zhang, James Randazzo, Neena B. Haider, Karen Blessing, Peter F. Kador; Retinal Changes in Galactose-Fed and Diabetic Mice Expressing Human Aldose Reductase and Green Fluorescent Protein in Retinal Capillary Pericytes. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3573. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Transgenetic mice containing green fluorescent protein (GFP) and human aldose reductase (hAR) in all vascular tissues containing smooth muscle actin have been developed. Here we show the effects of increased vascular hAR activity on growth factor and signaling changes in the retinas of these mice.

Methods: : Transgenic mice expressing GFP to aid in identification of retinal pericytes (SMAA-GFP) and expressing hAR to increase the levels of AR activity in pericytes (SMAA-hAR) were crossbred to develop mice with both attributes (SMAA-GFP-hAR). Diabetes was introduced by cross breeding with the diabetic Akita (Ins2Akita/J) mouse. Desired attributes in each was confirmed by genotyping. SMAA-GFP and SMAA-GFP-hAR mice treated +/- the aldose reductase inhibitor (ARI) AL1576 were fed 30% galactose diet for up to 4 months. Akita/SMAA-GFP and Akita/SMAA-GFP-hAR mice were treated +/- AL1576. Retinal changes were compared to age-matched SMAA-GFP mice (control group) fed normal rodent chow. Young S.D. rats were fed 50% galactose diet while streptozotocin induced diabetic rats were fed standard rodent chow. Groups of galactose-fed and diabetic rats were also treated with AL1576. Changes in growth factor and stress signaling expressions were evaluated by Western Blots. ERG changes in mice were conducted by standard methods.

Results: : Retinal expression of in the growth factors b-FGF, IGF-1, TGFβ, and signaling in P-c-Raf, P-Akt, P-SAPK/JNK, P- 44/42 MAPK generally increased in diabetics compared to control rats. These changes were normalized to control levels when treated with AL1576. In Akita/SMAA-GFP mice expression levels were similar to those observed in non-diabetic rats; however, retinal expression levels in Akita/SMAA-GFP-hAR mice appeared similar to those of diabetic rats and these levels were also normalized by AL1576. Changes in retinal expression levels were also observed with the galactose-fed mice and rats. ERGs in Akita/SMAA-GFP-hAR mice demonstrated a reduced b-wave that was increased by treatment with AL1576.

Conclusions: : In transgenic mice, increasing the retinal expression of hAR results in growth factor and signaling expression changes that mirror those of diabetic and galactosemic rats. Introduction of retinal hAR also results in functional ERG changes that are reversed by ARIs.

Keywords: diabetic retinopathy • signal transduction • transgenics/knock-outs 
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