Abstract
Aims/hypothesisDiabetic retinopathy is increasing in prevalence worldwide and is fast becoming a global epidemic and a leading cause of visual loss. Current therapies are limited, and the development of effective treatments for diabetic retinopathy requires a greater in-depth knowledge of disease progression and suitable modelling of diabetic retinopathy in animals. The aim of this study was to assess the early pathological changes in retinal morphology and neuronal, inflammatory and vascular features consistent with diabetic retinopathy in the ob/ob mouse model of type 2 diabetes, to investigate whether features similar to those in human diabetic retinopathy were present.MethodsMale and female wild-type (+/+), heterozygous (+/−) and homozygous (−/−) BTBR ob/ob mice were examined at 6, 10, 15 and 20 weeks of age. Animals were weighed and blood glucose was measured. TUNEL and brain-specific homeobox/POU domain protein 3A (BRN3A) markers were used to examine retinal ganglion cells. We used immunostaining (collagen IV and platelet endothelial cell adhesion molecule [PECAM]/CD31) to reveal retinal vessel degeneration. Spectral domain optical coherence tomography was used to reveal changes in the thickness and structure of the retinal layer. Vitreous fluorophotometry was used to investigate vascular permeability. A-waves, b-waves and oscillatory potentials were measured under photopic and scotopic conditions. Concanavalin A leucostasis and immunostaining with glial fibrillary acidic protein (GFAP) and ionised calcium-binding adapter molecule 1 (IBA-1) identified differences in inflammatory status. Paraffin sections and transmission electron microscopy were used to reveal changes in the thickness and structure of the retinal layer.ResultsFollowing the development of obesity and hyperglycaemia in 2-week-old and 3-week-old ob−/ob− mice, respectively (p < 0.001), early functional deficits (p < 0.001) and thinning of the inner retina (p < 0.001) were identified. Glial activation, leucostasis (p < 0.05) and a shift in microglia/macrophage phenotype were observed before microvascular degeneration (p < 0.05) and elevated vascular permeability occurred (p < 0.05).Conclusions/interpretationThe present characterisation of the development of diabetic retinopathy in the ob/ob mouse represents a platform that will enable the development of new therapies, particularly for the early stages of disease.
Highlights
Diabetic retinopathy, which occurs in both type 1 and type 2 diabetes, is fast becoming a worldwide epidemic
One major impediment to this is the lack of a well-characterised model of diabetic retinopathy in type 2 diabetes in which obesity is one of the main traits; such a model could drive a new mechanistic understanding and allow the validation of new therapeutic targets
The purpose of the current study is to provide an in-depth characterisation of the progression of diabetic retinopathy in BTBR ob/ob mice in terms of its vascular, neurodegenerative and inflammatory manifestations
Summary
Diabetic retinopathy, which occurs in both type 1 and type 2 diabetes, is fast becoming a worldwide epidemic. Most individuals with type 1 diabetes develop diabetic retinopathy, and a growing number of those with type 2 diabetes manifest it, with high blood sugar, insulin resistance and a relative lack of insulin for which limited therapies are currently available. The BTBR ob/ob mouse is a well-established, robust model of diabetic neuropathy [2] and diabetic nephropathy [3] in type 2 diabetes. Published data on these mice at 22 weeks of age suggest that they develop retinal thinning [4]. We initiated an indepth characterisation of the retinal phenotype of this model, aiming to describe the earliest pathology and define useful endpoints for pharmacology
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