Unfolded protein response is activated in aged retinas

An unfolded protein response (UPR) in addition to oxidative stress and the inflammatory response is known to be activated in age-related ocular disorders, such as macular degeneration, diabetic retinopathy, glaucoma, and cataracts. Therefore, we aimed to investigate whether healthy aged retinas display UPR hallmarks, in order to establish a baseline for the activated UPR markers for age-related ocular diseases. Using western blotting, we determined that the hallmarks of the UPR PERK arm, phosphorylated (p) eIF2a, ATF4, and GADD34, were significantly altered in aged vs. young rat retinas. The cleaved pATF6 (50) and CHOP proteins were dramatically upregulated in the aged rodent retinas, indicating the activation of the ATF6 UPR arm. The UPR activation was associated with a drop in rhodopsin expression and in the NRF2 and HO1 levels, suggesting a decline in the anti-oxidant defense in aged retinas. Moreover, we observed down-regulation of anti-inflammatory IL-10 and IL-13 and upregulation of pro-inflammatory RANTES in the healthy aged retinas, as measured using the Bio-plex assay. Our results suggest that cellular homeostasis in normal aged retinas is compromised, resulting in the concomitant activation of the UPR, oxidative stress, and inflammatory signaling. This knowledge brings us closer to understanding the cellular mechanisms of the age-related retinopathies and ocular disorders characterized by an ongoing UPR, and highlight the UPR signaling molecules that should be validated as potential therapeutic targets.