Abstract
Purpose:
In diabetic retinopathy a major cause of vision loss is macular edema. The etiology of macular edema has been tied to endothelial dysfunction of the inner blood-retina barrier. However, more recent studies have shown that dysfunction of the retinal pigment epithelium (RPE), which comprises the outer blood-retina barrier, also plays a role in this disease. Changes in protein acetylation have been shown to play a central role in pathophysiological responses to hyperglycemia. In this study, we investigate the effects of the HDAC inhibitor trichostatin A (TSA) on hyperglycemia-induced RPE dysfunction.
Methods:
Brown Norway rats (130-150g) were injected IP with 60 mg/kg of streptozotocin (STZ) dissolved in citrate buffer; controls were injected with buffer alone. Animals were considered diabetic with plasma glucose of 250 mg/dL or greater. Retinal thickness, plasma glucose, and weight were measured. Animals were treated with TSA (2.5 mg/kg BID IP, 10% DMSO) or vehicle control for 4 days before bleb injection. Subretinal blebs (1µL PBS) were created and reabsorption observed and measured via optical coherence tomography and rates of fluid resorption calculated.
Results:
In normoglycemic control rats, RPE fluid resorption rate was 8.92±1.19 ul*cm-2*hr-1(n=4). In diabetic rats, nine weeks after STZ injection, RPE fluid reabsorption was significantly (p< 0.05) reduced to 2.43±0.55 ul*cm-2*hr-1 (n=6). In diabetic rats, TSA treatment significantly increased fluid resorption rates to 8.11±1.54 (ul*cm-2*hr-1; n=7). In control rats TSA administration had no significant effect on RPE fluid reabsorption (8.068±1.81 ul*cm-2*hr-1; n=4). In diabetic rats, nine weeks after STZ injection retinal thickness increased by 5.21±1.45% (p<0.05; n=4). Diabetic rats treated with TSA exhibited a reduction in retinal thickness (4.38±1.20%; n=9); however, this change did not significantly differ from that observed in untreated diabetic rats.
Conclusions:
Acute TSA treatment normalized RPE fluid resorption in diabetic animals. While a trend towards reducing retinal thickness was measure in this diabetic model no significant change in thickness was measured with the TSA dosing utilized in these initial studies. These data provide evidence that decreases in protein acetylation plays a role in hyperglycemic-induced RPE dysfunction. However, it is not clear if the use of HDAC inhibitor alone will be efficacious in treating diabetic macular edema.