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K. K. Erickson, C. J. Barnstable, J. Tombran-Tink; A PEDF N-Terminal Peptide Protects Against Retinal Degeneration in the Ins2Akita Mouse Model of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1333.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is a major complication of Types I and II Diabetes. It affects approximately 50% of individuals suffering from diabetes and is the leading cause of visual impairment and blindness in working age Americans. DR treatment is currently limited to laser photocoagulation. In this study, the effects of PEDF, a well-characterized neuroprotective and anti-angiogenic polypeptide, on the pathology of diabetic retinopathy is investigated.
Male C57BL/6J Ins2Akita heterozygote mice were used in this study. After 4 to 20 weeks of hyperglycemia, mice were injected intravitreally with 1µl of 1µg/µl PEDF, 1µg/µl of an N-Terminal PEDF peptide, PEDF82-121, or PBS and sacrificed after 1 week. PEDF’s action on vascular permeability was determined using intravenous injection of FITC conjugated bovine serum albumin (FITC-BSA) and its effects on occludin and ZO-1 expression were monitored using specific antibodies to these junctional molecules. The expression of other markers of angiogenesis, PEDF, VEGF, VEGFR1, VEGFR2 and VEGFR3, were also examined in the control and PEDF treated animals. In addition, we studied microglial and astrocyte activation using IbA1 and GFAP, respectively. The overall effect of PEDF on retinal neuroprotection was analyzed further by determining the expression of caspase-3, by morphometric analysis of the thickness of various layers of the retina, and by TUNEL assay.
Ins2Akita mice have higher retinal parenchymal FITC-BSA fluorescence, increased expression of activated caspase-3 as well as reduction in the thickness of the inner plexiform layer, the inner nuclear layer, and a reduction in the number of cell bodies in the retinal ganglion cell layer. Intravitreal injection of PEDF or PEDF82-121 significantly reduced vascular permeability, increased the expression of ZO-1, decreased the expression of VEGFR3, GFAP, and caspase-3, prevented cell death, and offered long term protection to the retina with no noticeable side effects after 7 days.
PEDF and PEDF82-121 protect the retina from the insults of DR by modulating inflammatory, angiogenic, and cell death markers in the Ins2Akita mice. These studies provide an important first step towards understanding the role of PEDF in diabetic retinopathy.
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