Abstract
Purpose: :
The PI3K/Akt pathway regulates a number of important functions, such as cell survival, angiogenesis and inflammation, in the retina and the retinal pigment epithelium (RPE). The goal of the study was to determine age-related changes in the activities and functions of this pathway in the RPE.
Methods: :
Replicative senescence was used to induce in vitro aging of cultured human fetal RPE cells. Akt phosphorylation in response to serum, EGF and PDGF was measured by Western blot analyses. TNF and IL-1 beta-stimulated CCL2 (MCP-1) production was measured by real-time RT-PCR. Ex vivo PI3K activation in the retina and RPE was performed using posterior segment isolated from 1 year old mice.
Results: :
In cell culture, senescent RPE cells showed decreased PI3K activation and CCL2 produciton, and were less efficient in transducing the signals to downstream substrate proteins such as GSK3 beta. Similar results were observed in ex vivo activation. Inhibiting PI3K resulted in decreased CCL2 production, by mechanisms that were likely independent of NF-ΚB.
Conclusions: :
Aging of the RPE is associated with decreased PI3K/Akt signaling. Such change may render the retinal tissue more susceptible to age-related degeneration.
Keywords: age-related macular degeneration • phosphorylation • retinal pigment epithelium