Abstract
BackgroundInvestigations into the mechanism of diffuse retinal edema in diabetic subjects have been limited by a lack of animal models and techniques that co-localized retinal thickness and hydration in vivo. In this study we test the hypothesis that a previously reported supernormal central retinal thickness on MRI measured in experimental diabetic retinopathy in vivo represents a persistent and diffuse edema.Methodology/Principal FindingsIn diabetic and age-matched control rats, and in rats experiencing dilutional hyponatremia (as a positive edema control), whole central retinal thickness, intraretinal water content and apparent diffusion coefficients (ADC, ‘water mobility’) were measured in vivo using quantitative MRI methods. Glycated hemoglobin and retinal thickness ex vivo (histology) were also measured in control and diabetic groups. In the dilutional hyponatremia model, central retinal thickness and water content were supernormal by quantitative MRI, and intraretinal water mobility profiles changed in a manner consistent with intracellular edema. Groups of diabetic (2, 3, 4, 6, and 9 mo of diabetes), and age-matched controls were then investigated with MRI and all diabetic rats showed supernormal whole central retinal thickness. In a separate study in 4 mo diabetic rats (and controls), MRI retinal thickness and water content metrics were significantly greater than normal, and ADC was subnormal in the outer retina; the increase in retinal thickness was not detected histologically on sections of fixed and dehydrated retinas from these rats.Conclusions/SignificanceDiabetic male Sprague Dawley rats demonstrate a persistent and diffuse retinal edema in vivo, providing, for the first time, an important model for investigating its pathogenesis and treatment. These studies also validate MRI as a powerful approach for investigating mechanisms of diabetic retinal edema in future experimental and clinical investigations.
Highlights
There are few non-invasive treatment options for diffuse retinal edema (DRE) in patients with diabetes
Studies with albuminassociated tracers report damage to blood retinal barrier (BRB) prior to 3 mo of diabetes in male Sprague Dawley (SD) rats [8,12]. It remains unclear whether or not such early retinal thickening and/or loss of transcellular BRB integrity represent edema in male SD rats. We address this question by first determining if central retinal thickening persisted over time in diabetic male SD rats
We 1) confirmed a supernormal central retinal thickness diabetic male SD rats via MRI and extended these results to 2–9 mo of hyperglycemia, 2) validated the sensitivity and physiologic accuracy of new MRI methods for assessing central retinal water content and mobility [15], and 3) found first-time evidence that central retinal thickening in rats following 4 mo of diabetes is due to edema
Summary
There are few non-invasive treatment options for diffuse retinal edema (DRE) in patients with diabetes. Used metrics for retinal edema include retinal morphology/thickness (e.g., optical coherence tomography or histology), BRB integrity (e.g., leakage and accumulation of exogenous biomarkers, or damage to tight junction proteins), or the extent of isolated Muller cell swelling in response to an osmotic challenge [6,7,8,9]. Such assessments are generally incomplete since these biomarkers do not spatially co-localize changes in intraretinal thickness and water content in the same eye in vivo. In this study we test the hypothesis that a previously reported supernormal central retinal thickness on MRI measured in experimental diabetic retinopathy in vivo represents a persistent and diffuse edema
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