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Lasse DE Jensen, Zaheer Ali, Neil S Lagali, Robin A Kimmel; Pdx1-mutant zebrafish develop proliferative diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2510.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR), is the most common causes of vision impairment in the working-age population. Disease severity is intimately coupled with retinal neovascularization during progression to proliferative disease (proliferative diabetic retinopathy; PDR), but to date it has not been possible to study this process due to limitations in the available animal models. As such, there is a gap in our knowledge about what causes the switch to proliferative disease. Unlike other animals, retinal neovascularization may be induced in adult zebrafish, but whether diabetes could drive retinal neovascularization in zebrafish is not known. The purpose of this project was to test the hypothesis that recently characterized diabetic pdx1-mutant zebrafish develop PDR, thus constituting a long sought-after model of this common and severe disease.
Pdx1-mutant zebrafish, crossed with fluorescent reporters for detection of endothelial cells, pericytes, smooth muscle cells, glial cells and macrophages were used. These fish were investigated by immunohistochemistry, qPCR, western blot and by electron microscopy at 3, 6, 9 and 12 months of age.
Diabetic, pdx1-mutant fish exhibited clear signs of PDR already at 3 months of age, including increased vessel dilation and tortuosity, hypersprouting and disruption of endothelial tight junctions and contact with perivascular cells. These phenotypes became more severe over time leading to significant disruption of the retinal vasculature in 12-months old pdx1-mutant fish compared to controls. Robust retinal neovascularization was intimately coupled to a breakdown of the blood-retinal barrier (BRB) and disease severity was proportional to the degree and duration of hyperglycemia. Also progressive degeneration of photoreceptors were observed, the degree of which correlated to the severity of the neovascular phenotypes.
Retinal neovascularization, leakage and photoreceptor degeneration, is induced in long-term diabetic pdx-1 mutant zebrafish, resembling human PDR. Zebrafish therefore provide a strong alternative to mouse models for research into mechanisms underlying retinal angiogenesis under pathological situations in adults, and may be used to identify new targets for treatment of PDR in the future.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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