Aquaporin 5 Facilitates Corneal Epithelial Wound Healing and Nerve Regeneration by Reactivating Akt Signaling Pathway

Aquaporins (AQPs) are a highly conserved group of membrane proteins that play critical roles in water and small solute transport across epithelial and endothelial barriers. The aim of this study was to determine whether AQP5, a well-known water channel protein, also plays a role in corneal epithelial wound healing. AQP5 knockout (AQP5-/-) mice were generated using CRISPR/Cas9. A corneal wound healing model was established using epithelial debridement of corneas. The time to corneal epithelial and nerve regeneration was significantly delayed in the AQP5-/- mice. Reduction in Ki-67-positive cells and nerve growth factor (NGF) expression was confirmed in the AQP5-/- mice during healing. Epithelial and nerve regeneration rates were significantly increased in the AQP5-/- mice after treatment with NGF, which was accompanied by recovered levels of phosphorylated Akt. NGF treatment also improved the recovery of corneal nerve fiber density and sensitivity in the AQP5-/- mice. While the promotion of NGF induced corneal epithelial and nerve regeneration, Akt inhibitor reversed Akt reactivation. A significant impairment of corneal wound healing in the AQP5-/- mice resulted from distinct defects in corneal epithelial cell proliferation and nerve regeneration. These results provide evidence for the involvement of aquaporin in cell proliferation and suggest that AQP5 induction could be a potential therapy for accelerating the resurfacing of corneal defects. (Am J Pathol 2021, 191: 1974-1985; https://doi.org/10.1016/j.ajpath.2021.07.010)