Abstract
Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders.
Highlights
Diabetes is the leading cause of blindness among the working-age population,[1] with approximately one-third of diabetic patients displaying signs of diabetic retinopathy (DR).[2,3] Clinically, DR is classified into two progressive stages
Cadavers are currently the only source of human retinal neurons affected by proliferative DR (PDR), so a murine model neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy would be a powerful tool for testing the progressive clinical phenotype, neovascularization and ischemia
To determine whether HIF1α was active in human PDR, we collected vitreous from patients with DR, as it has been shown that the retina releases proteins into the vitreous.[26,27]
Summary
Diabetes is the leading cause of blindness among the working-age population,[1] with approximately one-third of diabetic patients displaying signs of diabetic retinopathy (DR).[2,3] Clinically, DR is classified into two progressive stages. Most available mouse models of DR are inadequate, because within the lifespan of the diabetic animals, they develop only a mild, nonproliferative disease.[6,7] For example, the O2-induced retinopathy and Kimba/Akimba vascular endothelial growth factor (VEGF) transgenic mouse models have been useful for studying retinopathy of prematurity and vascular leakage, in these mice, neovascularization spontaneously regresses and so limits testing of many therapeutic hypotheses.[2,8,9,10,11,12,13] the newest murine model for DR (a Per[2] mutant) displays gene expression patterns similar to DR human patients, the mice do not develop the vascular abnormalities characteristic of human PDR.[14]
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