Ultraviolet (UV) radiation and reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelium (RPE) cells by inducing cell apoptosis, which is the main cause of age-related macular degeneration (AMD). The mechanism by which UV/ROS induces RPE cell death is not fully addressed. Here, we observed the activation of a ceramide-endoplasmic reticulum (ER) stress-AMP activated protein kinase (AMPK) signaling axis in UV and hydrogen peroxide (H2O2)-treated RPE cells. UV and H2O2 induced an early ceramide production, profound ER stress and AMPK activation. Pharmacological inhibitors against ER stress (salubrinal), ceramide production (fumonisin B1) and AMPK activation (compound C) suppressed UV- and H2O2-induced RPE cell apoptosis. Conversely, cell permeable short-chain C6 ceramide and AMPK activator AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide) mimicked UV and H2O2’s effects and promoted RPE cell apoptosis. Together, these results suggest that UV/H2O2 activates the ceramide-ER stress-AMPK signaling axis to promote RPE cell apoptosis.

Glutamate is a major excitatory neurotransmitter in the retina. Glutamate neurotoxicity has been implicated in the pathogenesis of several ocular diseases. Aquaporin 4 (AQP4) is a water-selective membrane transport protein, and its knockout could alter retinal neuron excitability. However, the effect of AQP4 knockout on glutamate metabolism is still unclear in the retina. Here, we reported that the retinas in AQP4 knockout mice showed higher glutamate levels than that in wild-type mice upon light damage. AQP4 knockout could result in accelerated apoptosis of retinal cells, increased reactive gliosis, and attenuated survival of RGCs in response to light damage. Moreover, AQP4 knockout could affect the expression pattern of glutamate metabolism-related proteins such as GLAST and GS. Taken together, this study revealed a novel role of AQP4 in regulating glutamate metabolism. Pharmacological manipulation of AQP4 function may represent as a potent therapeutic target in the treatment of neurological ocular disorders.

Nerve distal axon injury-induced Wallerian degeneration is significantly delayed in Wallerian degeneration slow (Wlds) mutant mice, although the associated mechanisms are not completely clear and the role of Wlds in retinal ganglion cell (RGC) body damage is not fully understood. In the present study, a Wallerian degeneration model was established in wild-type (WT) and Wlds mutant mice by creating mechanical injury in the optic nerves. Wallerian degeneration and RGC body collapse were observed to be significantly delayed in the Wlds mice. Electroretinograms (ERG) and visual evoked potentials (VEPs) in Wlds mice were also significantly improved at the earlier stages (one week) following injury. The retina immunohistochemistry results showed that Wlds mice had more ordered cells and improved inner granular cell layer arrangement compared with the WT mice. Optic nerve Luxol Fast Blue (LFB) staining showed greater axon demyelination in WT mice than in Wlds mice. A large number of apoptotic cells were also observed in the WT mice. The present results suggest that the Wlds gene may also protect the RGC body following nerve injury.