Activation of signaling pathways and stress-response genes in an experimental model of retinal detachment.

摘要

PURPOSE: Despite the high metabolic demands of the neural retina, its detachment from the retinal pigment epithelium does not lead to immediate death for most of the cells. This study was undertaken to test the hypothesis that intrinsic protective mechanisms are activated in the neural retina during early stages of retinal detachment. METHODS: Retinal detachments were created in Brown Norway rats by injection of 1% hyaluronic acid into the subretinal space. Gene expression profiles of retinas detached for 24 hours were generated with a gene microarray (rat U34 GeneChips; Affymetrix, Santa Clara, CA) and compared to the profiles from control attached retinas in a robust multiarray protocol and false-discovery-rate analysis. Changes in individual, differentially expressed genes were validated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. Additional qRT-PCR and immunoblot analyses were performed for additional selected genes. RESULTS: Genome-wide expression profiling revealed 27 genes that are differentially expressed in retinas detached for 24 hours. In silico analysis and functional clustering suggested that most genes belonged to three signaling pathways: interleukin-6/STAT, transforming growth factor-beta/Smad, and aryl hydrocarbon receptor oxidative stress response. Additional analyses of selected genes from these pathways demonstrated a time-dependent increase in their expression in detached retinas. CONCLUSIONS: Retinal detachment results in the early activation of stress-response genes and specific signaling pathways. This adaptive response may enable the photoreceptor cells to survive the acute phase of a retinal detachment, and it is the breakdown of these protective mechanisms in chronic disease that leads to the ultimate death of the cell.