Expression Profiling after Retinal Detachment and Reattachment : A Possible Role for Aquaporin-0

Retinal detachment (RD) is a sight-threatening condition that occurs when the neural retina physically separates from the retinal pigment epithelium (RPE). In clinical and animal models of RD, photoreceptors undergo apoptotic cell death and the retina undergoes secondary changes such as gliosis, hypertrophy, and synaptic remodeling.1–3 RD-induced changes in retinal gene and protein expression are thought to play important roles in stimulating stress-induced intrinsic neuroprotective mechanisms in the retina and in delaying or compromising the recovery of vision even after successful anatomic reattachment.4–7 Nearly complete RD can be induced in mice by transretinal injection of saline into the subretinal space. This procedure creates a detachment similar to rhegmatogenous detachments in humans, whereby a tear in the retina allows fluid to accumulate between the RPE and the retina. We have shown that the retina spontaneously reattaches within 1 to 2 days after detachment, but this reattachment is associated with massive retinal in-foldings.8 Complete reattachment occurs 7 days after the initial detachment, but retinal function, as measured by electroretinography (ERG), is only approximately 50% of normal even though the retina appears to be anatomically reattached and morphologically intact. This resolution of RD in our animal model more closely mimics the exudative form of human RD. In humans, fluid accumulates between the RPE and the retina without any tear or break. Even at 14 days after detachment, the ERG is only approximately 60% of normal, and full recovery is not observed electroretinographically until 2 months after the initial detachment. We also demonstrated that the administration of the P2Y2 receptor agonist INS37217 in this RD model resulted in almost complete recovery of retinal ERG function by 10 days after detachment, presumably through stimulating fluid reabsorption across the RPE and perhaps through some other direct neurorestorative effects on the retina.8,9 Because of the relatively long time lag between full anatomic reattachment (approximately 7 days) and full recovery of ERG function (approximately 2 months), this model represents a useful system for studying the delayed recovery of neurosensory function after physical traumatic injury to the retina. Although this model does not perfectly mimic one specific form of RD, it may provide insight into the mechanisms underlying the delayed or incomplete recovery of normal visual function frequently seen in RD patients after otherwise successful reattachment of the retina. In this study, we evaluated the effects of RD and spontaneous reattachment in the absence and presence of INS37217 on retinal gene expression to determine which genes are involved in response to an induced detachment and subsequent reattachment occurring in response to a pharmacologic agent known to hasten RD and recovery. Here we identified several genes involved in these response pathways that appeared to be likely candidates for accelerating the process of reattachment and perhaps ERG recovery. Based on our microarray screen, we evaluated the potential role for aquaporin-0 (AQP-0) as a direct mediator involved in the response to and recovery from RD. Expression of AQP-0 was previously thought to be specific to the lens, but we demonstrate its expression in retinal cells. Furthermore, we show that the loss of AQP-0 in mice has deleterious effects on the transmission of phototransduction signals, indicating an essential physiological function for AQP-0 in the retina.