March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Genetic Deletion or Pharmacological Inhibition of Aldose Reductase Protects the Retina in a Mouse Model of Ischemia-induced Retinopathy
Author Affiliations & Notes
  • Zhongjie Fu
    Eye Institute,
    The University of Hong Kong, Hong Kong, Hong Kong
  • Suk-Yee Li
    Eye Institute,
    The University of Hong Kong, Hong Kong, Hong Kong
  • Sookja K Chung
    Anatomy,
    Research Center of Heart, Brain, Hormone and Healthy Aging,
    The University of Hong Kong, Hong Kong, Hong Kong
  • David Wong
    Eye Institute,
    The University of Hong Kong, Hong Kong, Hong Kong
  • Amy C. Lo
    Eye Institute,
    Research Center of Heart, Brain, Hormone and Healthy Aging,
    The University of Hong Kong, Hong Kong, Hong Kong
  • Footnotes
    Commercial Relationships  Zhongjie Fu, None; Suk-Yee Li, None; Sookja K Chung, None; David Wong, None; Amy C. Lo, None
  • Footnotes
    Support  University Development Fund & Seed Funding for Basic Research from The University of Hong Kong
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 5883. doi:
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      Zhongjie Fu, Suk-Yee Li, Sookja K Chung, David Wong, Amy C. Lo; Genetic Deletion or Pharmacological Inhibition of Aldose Reductase Protects the Retina in a Mouse Model of Ischemia-induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5883.

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

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Abstract

Purpose: : Retinal neovascularization is a major pathologic process leading to blindness in many ocular diseases including retinopathy of prematurity. Oxidative stress has been reported to be highly related to its pathogenesis. We previously demonstrated that genetic deletion or pharmacological inhibition of aldose reductase (AR), a rate limiting enzyme in the polyol pathway, prevented oxidative stress and blood vessel leakage in ischemic retina. Here, we assessed the effects of AR deletion and inhibition on retinal injury using a mouse model of oxygen-induced retinopathy (OIR).

Methods: : Wild-type (WT) and AR-deficient mouse retinae were compared. Seven-day-old pups with their nursing dams were exposed to 75% oxygen for five days (P7-12) and then returned to room air (P12-17). Fidarestat (AR inhibitor, 2mg/kg body weight in dH2O) or vehicle (dH2O) was given daily i.p. after hyperoxia exposure. On P17, the mouse retinae were isolated and processed for histological, immunohistochemical and Western blotting experiments. Vascular changes including vaso-obliteration, neovascularization and blood vessel leakage were examined. Oxidative stress was assessed using antibodies against nitrotyrosine (NT) and poly(ADP-ribose) (PAR). Macroglial and microglial responses were investigated by analysis of immunoreactivity against glial fibrillary acidic protein (GFAP) and Iba1, respectively. Western blotting for VEGF, p-Erk1/2 and p-Akt was performed.

Results: : Significantly reduced vaso-obliterated area, early revascularization, attenuated neovascularization, and decreased blood vessel leakage were observed in AR-deficient OIR retinae when compared with WT OIR retinae. Significantly reduced vaso-obliteration and neovascularization were also present with Fidarestat administration. In addition, increased NT immunoreactivity in INL and PAR nuclear translocation in GCL were observed in WT OIR retinae but these changes were not apparent in AR-deficient OIR retinae. Moreover, less astrocytic immunoreactivity, reduced Müller cell gliosis, significantly reduced activated microglia in central avascular area, and significantly elevated activated microglia in neovascular area were observed in AR-deficient OIR retinae. Furthermore, there was also a significant reduction in induced expression of VEGF, p-Erk1/2 and p-Akt (molecules that are involved in endothelial cell proliferation and migration) in AR-deficient OIR retinae.

Conclusions: : Our observations indicated that genetic deletion or pharmacological inhibition of AR protected the retinal vasculature in a mouse model of OIR. AR may be a potential therapeutic target in ischemia-induced retinopathy.

Keywords: ischemia • neovascularization • microglia 
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