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Rithwick Rajagopal, Sheng Zhang, Christina Oberlin, Clay F. Semenkovich; Rod Visual Transduction is a Determinant of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2019;60(9):982.
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© ARVO (1962-2015); The Authors (2016-present)
Because of their high metabolic demands, photoreceptors may be particularly susceptible to metabolic disease such as diabetes. Conditions causing rod photoreceptor degeneration are associated with protection from diabetic retinopathy, suggesting rods are necessary for this disease. Here, we hypothesized that rod visual-evoked activity, not the presence of rods themselves, drives the development of diabetic retinopathy.
We studied two murine models of diabetic retinopathy and their appropriate littermate controls: streptozotocin (STZ) and Leprdb/db (db/db). In the STZ model, diabetes was induced at 8 weeks. In both models, experiments were performed between 6 and 9 months of age. Diabetes was confirmed when fasting plasma glucose became persistently elevated (>250 mg/dL). In db/db and STZ mice, blockade of visual activity in intact photoreceptors was achieved by visual deprivation in constant dark housing, beginning at 3 months of age. Mice deficient in expression of rod transducin (gnat1-/-) or retinoid isomerohydrolase (rpe65-/-) were used to interrogate effects of these non-degenerative mutations blocking visual transduction on diabetic retinopathy in the STZ model. In subgroups, we evaluated whole retina gene expression of vasoactive and inflammatory intermediates, electroretinography, and capillary morphometry after trypsin digest.
Diabetes-induced upregulation of transcripts for icam1, inos and gfap was prevented by visual deprivation in STZ and db/db mice and by rpe65-/- or gnat1-/- mutations in the STZ model. Visual deprivation in dark housing prevented delays in scotopic oscillatory potential timing observed in db/db mice kept in normal light:dark cycles. After sustained exposure to STZ-induced diabetes, rpe65-/- and gnat1-/- mice showed significantly fewer atrophic capillaries than non-diabetic littermates. In both STZ and db/db models, mice subjected to prolonged visual deprivation had similar degrees of fasting hyperglycemia as their littermates who were kept in normal light:dark cycles.
Blockade of phototransduction in type I and II diabetic mice mitigates development of molecular, physiologic, and histologic pathophenotypes characteristic of mouse diabetic retinopathy. These results suggest that certain aspects of rod photoreceptor visual-evoked activity are permissive for the development of diabetic retinopathy.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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