September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Blockade of Angiotensin II retards the progression of diabetic retinopathy through downregulating Muller cell-derived VEGF
Author Affiliations & Notes
  • PENG QIN
    Ophthalmology, The University of Hong Kong, Hong Kong, Hong Kong
  • Amy CY Lo
    Ophthalmology, The University of Hong Kong, Hong Kong, Hong Kong
    Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, Hong Kong, Hong Kong
  • Ian Wong
    Ophthalmology, The University of Hong Kong, Hong Kong, Hong Kong
    Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, Hong Kong, Hong Kong
  • Footnotes
    Commercial Relationships   PENG QIN, None; Amy Lo, None; Ian Wong, None
  • Footnotes
    Support  Seed Funding Programme for Basic Research (project no: 201310159038), The University of Hong Kong
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2119. doi:
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      PENG QIN, Amy CY Lo, Ian Wong; Blockade of Angiotensin II retards the progression of diabetic retinopathy through downregulating Muller cell-derived VEGF. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2119.

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

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Abstract

Purpose : The intraocular Angiotensin II (Ang II) has long been viewed as a pro-inflammatory factor released in response to hyperglycemia and may contribute to the pathogenesis of diabetic retinopathy. We aimed to determine if antagonism of diabetes-induced Ang II by its type I receptor blocker, Candesartan, can normalize the elevated pathogenic Vascular Endothelial Growth Factor (VEGF) and its associated retinal pathological changes in experimental diabetic retinopathy.

Methods : Candesartan (0.1ug/g/day or 1.0ug/g/day in drinking water) was given to Ins2Akita/+ mice, a spontaneous diabetes mouse model. Vehicle-treated (0.1% DMSO) Ins2Akita/+ mice and their wildtype littermates, Ins2+/+ mice, were used as controls. Retinal function was assessed by scotopic ERG. After 12, 22 or 32 weeks of hyperglycemia with or without Candesartan treatment, vascular pathologic alterations including the expression of VEGF, Occludin and ZO-1, leukostasis as well as vascular permeability in the retina were evaluated. Astrocyte morphology was examined by glial fibrillary acidic protein (GFAP) immunohistochemistry. Microglia activation was determined by co-localization of CD68 and ionized calcium-binding adapter molecule 1 (iba-1). As the cellular origin of pathogenic VEGF was thought to be Muller cell, we used primary cultured Muller cell harvested from Ins2+/+ mice to investigate the effect of Ang II and its inhibition on VEGF expression.

Results : Vehicle-treated Ins2Akita/+ mice showed the following diabetes induced abnormalities (p<0.05) when compared with age-matched wildtype littermates: decreased b-wave amplitude in scotopic ERG, increased VEGF expression, reduced level and redistribution of Occludin and ZO-1, enhanced leukostasis, vascular leakage, microglia activation and astrocytic atrophy. Candesartan-treated Ins2Akita/+ mice (either dose) exhibited attenuation of the aforementioned pathological alterations (p<0.05) when compared with vehicle-treated Ins2Akita/+ mice. In in vitro studies, Ang II upregulated Muller cell-derived VEGF expression at both transcriptional and translational level (p<0.01), which was normalized by treatment with Candesartan (p<0.01).

Conclusions : Treatment with Candesartan ameliorated hyperglycemia-induced retinal dysfunction, vascular leakage, inflammation, and glia atrophy, possibly by downregulating pathogenic Muller cell-derived VEGF.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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