Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial Cells
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 (AM...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/22/8818 |
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| author | Diwa Koirala Sarka Beranova-Giorgianni Francesco Giorgianni |
| author_facet | Diwa Koirala Sarka Beranova-Giorgianni Francesco Giorgianni |
| author_sort | Diwa Koirala |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T14:40:40Z |
| format | Article |
| id | doaj.art-28d35af635e14a119e21a03e75ca5848 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:40:40Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-28d35af635e14a119e21a03e75ca58482023-11-20T21:49:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012122881810.3390/ijms21228818Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial CellsDiwa Koirala0Sarka Beranova-Giorgianni1Francesco Giorgianni2Department of Pharmaceutical Sciences; The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Pharmaceutical Sciences; The University of Tennessee Health Science Center, Memphis, TN 38163, USADepartment of Pharmaceutical Sciences; The University of Tennessee Health Science Center, Memphis, TN 38163, USAIn 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.https://www.mdpi.com/1422-0067/21/22/8818retinal pigment epitheliumoxidized LDLtranscriptomeoxidative stressdrusen |
| spellingShingle | Diwa Koirala Sarka Beranova-Giorgianni Francesco Giorgianni Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial Cells International Journal of Molecular Sciences retinal pigment epithelium oxidized LDL transcriptome oxidative stress drusen |
| title | Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial Cells |
| title_full | Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial Cells |
| title_fullStr | Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial Cells |
| title_full_unstemmed | Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial Cells |
| title_short | Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial Cells |
| title_sort | early transcriptomic response to oxldl in human retinal pigment epithelial cells |
| topic | retinal pigment epithelium oxidized LDL transcriptome oxidative stress drusen |
| url | https://www.mdpi.com/1422-0067/21/22/8818 |
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