The membrane-bound water channel aquaporin-4 plays a significant role in the regulation of water movement within the retina. In retinal ischemia-reperfusion injury, changes in the expression and localization of aquaporin-4 have been reported. Previous studies also suggest that the internalization of several membrane-bound proteins, including aquaporin-4, may occur with or without lysosomal degradation. In this study, the internalization of aquaporin-4 was detected in the ischemic rat retina via double immunofluorescence labeling. Specifically, both aquaporin-4 and the mannose-6-phosphate receptor co-localized post-ischemic injury (10,30 and 60 min). The same results were found during a 12-h reperfusion window (2, 4 and 8 h, respectively) following 60 min of ischemia. Moreover, the co-expression of aquaporin-4 and lysosomal-associated membrane protein-1 was observed at 1-12 h of reperfusion, with co-expression increasing followed by a gradual decrease. These combined findings suggest that AQP4 is internalized in the ischemic-reperfused retina, and the lysosome is involved in degrading the internalized aquaporin-4 during the reperfusion phase. Both the internalization of aquaporin-4 and its lysosomal degradation may serve as valuable therapeutic targets for managing ischemic-reperfused retinal injury. (C) 2012 Elsevier Ireland Ltd. All rights reserved.