In the sub-retinal pigment epithelium (sub-RPE) space of the aging macula, deposits of oxidized phospholipids, oxidized derivatives of cholesterol and associated oxidized low-density lipoproteins (OxLDL) are considered contributors to the onset and development of age-related macular degeneration (AMD). We investigated the gene expression response of a human-derived RPE cell line exposed for short periods of time to non-cytotoxic levels of OxLDL or LDL. In our cell model, treatment with OxLDL, but not LDL, generated an early gene expression response which affected more than 400 genes. Gene pathway analysis unveiled gene networks involved in the regulation of various cellular functions, including acute response to oxidative stress via up-regulation of antioxidative gene transcripts controlled by nuclear factor erythroid-2 related factor 2 (NRF2), and up-regulation of aryl hydrocarbon receptor-controlled detoxifying gene transcripts. In contrast, circadian rhythm-controlling genes and genes involved in lipid metabolism were strongly down-regulated. Treatment with low-density lipoprotein (LDL) did not induce the regulation of these pathways. These findings show that RPE cells are able to selectively respond to the oxidized forms of LDL via the up-regulation of gene pathways involved in molecular mechanisms that minimize cellular oxidative damage, and the down-regulation of the expression of genes that regulate the intracellular levels of lipids and lipid derivatives. The effect on genes that control the cellular circadian rhythm suggests that OxLDL might also disrupt the circadian clock-dependent phagocytic activity of the RPE. The data reveal a complex cellular response to a highly heterogeneous oxidative stress-causing agent such as OxLDL commonly present in drusen formations.
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