Retinal oxidative stress activates the NRF2/ARE pathway: An early endogenous protective response to ocular hypertension

Abstract

Oxidative stress contributes to degeneration of retinal ganglion cells and their axons in glaucoma, a leading cause of irreversible blindness worldwide, through sensitivity to intraocular pressure (IOP). Here, we investigated early elevations in reactive oxygen species (ROS) and a role for the NRF2-KEAP1-ARE endogenous antioxidant response pathway using microbead occlusion to elevate IOP in mice. ROS levels peaked in the retina at 1- and 2-wks following IOP elevation and remained elevated out to 5-wks. Phosphorylation of NRF2 and antioxidant gene transcription and protein levels increased concomitantly at 2-wks after IOP elevation, along with phosphorylation of PI3K and AKT. Inhibiting PI3K or AKT signaling prevented NRF2 phosphorylation and reduced transcription of antioxidant-regulated genes. Ocular hypertensive mice lacking Nrf2 had elevated ROS and a diminished increase in antioxidant gene expression. They also exhibited earlier axon degeneration and loss of visual function. In conclusion, the NRF2-KEAP1-ARE pathway is endogenously activated early in ocular hypertension due to phosphorylation of NRF2 by the PI3K/AKT pathway and serves to slow the onset of axon degeneration and vision loss in glaucoma. These data suggest that exogenous activation of this pathway might further slow glaucomatous neurodegeneration.

Keywords: Antioxidant response element; Glaucoma; Nrf2; Optic nerve; Oxidative stress; Retinal ganglion cell.