Deletion of REDD1 Prevents Hyperglycemia-Induced Reactive Oxygen Species Accumulation and Retinal Cell Death

Abstract

Apoptosis of retinal neurons is accelerated by diabetes and the onset of increased cell death occurs early in disease progression. The present study was designed to evaluate molecular defects that contribute to diabetes-induced neuroretinal apoptosis and visual dysfunction. We recently demonstrated that the stress response protein REDD1 is induced by hyperglycemia in the retina of diabetic mice in a manner that contributes to neuronal cell death and visual dysfunction. One potential mechanism whereby REDD1 promotes neuronal apoptosis is through upregulation of reactive oxygen species (ROS), as the protein forms a pro-oxidant complex. In the retina of streptozotocin-induced diabetic mice, ROS levels, neuronal cell death, and REDD1 expression were increased concomitant with attenuation of contrast sensitivity thresholds, as assessed by behavioral optomotry. In R28 retinal cells in culture, hyperglycemic conditions increased REDD1 expression, ROS levels, and cell death. However, addition of the antioxidant N-acetyl-L-cysteine (NAC) to culture medium was sufficient to prevent the increase in ROS and cell death in response to hyperglycemic conditions. Moreover, REDD1-deficient cells did not exhibit increased ROS or cell death in response to hyperglycemic conditions. Similarly, in REDD1-deficient diabetic mice, ROS levels and cell death in retina were similar to that observed in nondiabetic mice. Finally, oral administration of NAC improved contrast sensitivity in diabetic mice relative to vehicle treated diabetic controls, demonstrating a key role for ROS levels in diabetes-induced visual dysfunction. Overall, the findings support therapeutic approaches targeting REDD1 and ROS production in the prevention of diabetes-induced visual dysfunction. Disclosure W.P. Miller: None. A. Toro: None. M.D. Dennis: None.