Modeling the Progression of Diabetic Retinopathy Using the BXD79 Mouse Strain

Abstract

Purpose : Diabetic retinopathy (DR) is a microvascular disease associated with diabetes mellitus complications. The alterations in blood flow and vasodilation accompanying the erratic changes in blood sugar associated with DR can affect the vasculature and neurons of the retina, resulting in blindness. Utilizing animal models elicits a better understanding and permits further investigation of the genetic, cellular, and molecular mechanisms of multiple retinal degenerative diseases observed in humans. However, diseases with complex etiologies such as DR, can be difficult to model in animals often requiring initiating the disease state with some form of insult such as streptozotocin treatment to kill pancreatic islet cells. We have uncovered a naturally occurring, spontaneous model of DR, the BXD79 mouse, which displays phenotypes of high blood sugar, obesity, vascular leakage, cataracts, and retinal degeneration. This study seeks to investigate the etiology and pathology of DR in the BXD79 model.

Methods : BXD79 and age-matched C57B/6J controls underwent retinal functional examinations including electroretinograms (ERG), optokinetic nystagmography (OKN), optical coherence tomography (OCT), and funduscopy/fluorescein angiography (F/FA) every 3 months beginning at 6 months of age until 18 months.

Results : ERGs reveal improper retinal function by 9 months denoted by the reduction in a-wave and b-wave amplitudes and continue to diminish until 18 months. Reduction in visual acuity and contrast sensitivity observed by OKN also indicate visual function abnormalities. Additionally, retinal thinning including regions of the photoreceptor layers and the nerve fiber layer was observed by OCT while exudative vasculature also began at 9 months and progressed through 18 months as observed by F/FA.

Conclusions : In summary, this spontaneous model of DR contributes to a deeper understanding of the etiology and pathology of this disease when examining the related phenotypes, blood vessels, and neurons of the retina. Functional examination results suggest a progressive reduction in retinal function, and disruption of retinal and vascular integrity from 9 to 18 months. Despite DR being a complex disease to model, further exploration into its mechanisms using the BXD79 model may aid in advancing therapeutic interventions for humans.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.