Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response

Robert M Brucklacher,Sarah K Bronson,Alistair J Barber,Kathryn F Lanoue,Cheng-Mao Lin,Heather D Vanguilder,David A Antonetti,Georgina V Bixler,Thomas W Gardner,Kruti M Patel,Willard M Freeman

doi:10.1186/1755-8794-1-26

Robert M Brucklacher, Sarah K Bronson + Show 9 more

Open Access

https://doi.org/10.1186/1755-8794-1-26

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Abstract

BackgroundDespite advances in the understanding of diabetic retinopathy, the nature and time course of molecular changes in the retina with diabetes are incompletely described. This study characterized the functional and molecular phenotype of the retina with increasing durations of diabetes.ResultsUsing the streptozotocin-induced rat model of diabetes, levels of retinal permeability, caspase activity, and gene expression were examined after 1 and 3 months of diabetes. Gene expression changes were identified by whole genome microarray and confirmed by qPCR in the same set of animals as used in the microarray analyses and subsequently validated in independent sets of animals. Increased levels of vascular permeability and caspase-3 activity were observed at 3 months of diabetes, but not 1 month. Significantly more and larger magnitude gene expression changes were observed after 3 months than after 1 month of diabetes. Quantitative PCR validation of selected genes related to inflammation, microvasculature and neuronal function confirmed gene expression changes in multiple independent sets of animals.ConclusionThese changes in permeability, apoptosis, and gene expression provide further evidence of progressive retinal malfunction with increasing duration of diabetes. The specific gene expression changes confirmed in multiple sets of animals indicate that pro-inflammatory, anti-vascular barrier, and neurodegenerative changes occur in tandem with functional increases in apoptosis and vascular permeability. These responses are shared with the clinically documented inflammatory response in diabetic retinopathy suggesting that this model may be used to test anti-inflammatory therapeutics.

Highlights

Despite advances in the understanding of diabetic retinopathy, the nature and time course of molecular changes in the retina with diabetes are incompletely described
As predicted by earlier assessments, diabetic rats were hyperglycemic and underweight in comparison to control rats (Table 1). These data and the methods described are representative of experiments performed by the Penn State JDRF Animal Models Core since 2003 [14]
Vascular permeability and apoptosis Retinal vascular permeability, as measured by FITC-BSA incorporation into nonvascular retinal tissue, was unchanged at 1 month of diabetes but was significantly increased (52%, p < 0.05) after 3 months of diabetes (Table 2)

Summary

Introduction

Despite advances in the understanding of diabetic retinopathy, the nature and time course of molecular changes in the retina with diabetes are incompletely described. This study characterized the functional and molecular phenotype of the retina with increasing durations of diabetes. Diabetic retinopathy (DR) is one of the most debilitating diabetic complications. DR is best prevented by intensive glycemic control as demonstrated by the Diabetes Control and Complications Trial (DCCT) study [1]. Established treatments of DR are limited to panretinal laser photocoagulation therapy and control of hypertension [2]. The ability to achieve intensive glycemic control through insulin is limited by hypoglycemia, and given that islet cell transplants are not widely available, pharmacotherapies for prevention and treatment of DR are needed. Continued development is needed for DR therapies

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