Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Transcriptome Analysis of Long-Term Exposure to Blue Light in Retinal Pigment Epithelial Cells

  • Jin, Hong Lan (Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Molecular Medicine Research Center, Yanbian University, College of Pharmacy, Yanbian University) ;
  • Jeong, Kwang Won (Gachon Research Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University)
  • Received : 2021.10.07
  • Accepted : 2022.01.05
  • Published : 2022.05.01
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Abstract

Dry age-related macular degeneration (AMD) is a type of progressive blindness that is primarily due to dysfunction and the loss of retinal pigment epithelium (RPE). The accumulation of N-retinylidene-N-retinylethanolamine (A2E), a by-product of the visual cycle, causes RPE and photoreceptor degeneration that impairs vision. Genes associated with dry AMD have been identified using a blue light model of A2E accumulation in the retinal pigment epithelium and transcriptomic studies of retinal tissue from patients with AMD. However, dry macular degeneration progresses slowly, and current approaches cannot reveal changes in gene transcription according to stages of AMD progression. Thus, they are limited in terms of identifying genes responsible for pathogenesis. Here, we created a model of long-term exposure to identify temporally-dependent changes in gene expression induced in human retinal pigment epithelial cells (ARPE-19) exposed to blue light and a non-cytotoxic dose of A2E for 120 days. We identified stage-specific genes at 40, 100, and 120 days, respectively. The expression of genes corresponding to epithelial-mesenchymal transition (EMT) during the early stage, glycolysis and angiogenesis during the middle stage, and apoptosis and inflammation pathways during the late stage was significantly altered by A2E and blue light. Changes in the expression of genes at the late stages of the EMT were similar to those found in human eyes with late-stage AMD. Our results provide further insight into the pathogenesis of dry AMD induced by blue light and a novel model in vitro with which relevant genes can be identified in the future.

Keywords

Acknowledgement

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1A2C1011132) to K.W.J. and National Natural Science Foundation of China (No. 81960667) to H.L.J.

References

  1. Al Gwairi, O., Thach, L., Zheng, W., Osman, N. and Little, P. J. (2016) Cellular and molecular pathology of age-related macular degeneration: potential role for proteoglycans. J. Ophthalmol. 2016, 2913612. https://doi.org/10.1155/2016/2913612
  2. Alaimo, A., Linares, G. G., Bujjamer, J. M., Gorojod, R. M., Alcon, S. P., Martinez, J. H., Baldessari, A., Grecco, H. E. and Kotler, M. L. (2019) Toxicity of blue led light and A2E is associated to mitochondrial dynamics impairment in ARPE-19 cells: implications for age-related macular degeneration. Arch. Toxicol. 93, 1401-1415. https://doi.org/10.1007/s00204-019-02409-6
  3. Boutzen, J., Valet, M., Alviset, A., Fradot, V., Rousseau, L., Francais, O., Picaud, S. and Lissorgues, G. (2020) Impedance spectroscopy study of the retinal pigment epithelium: application to the monitoring of blue light exposure effect on A2E-loaded in-vitro cell cultures. Biosens. Bioelectron. 161, 112180. https://doi.org/10.1016/j.bios.2020.112180
  4. Ferrington, D. A., Sinha, D. and Kaarniranta, K. (2016) Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration. Prog. Retin. Eye Res. 51, 69-89. https://doi.org/10.1016/j.preteyeres.2015.09.002
  5. Ferris, F. L., 3rd, Wilkinson, C. P., Bird, A., Chakravarthy, U., Chew, E., Csaky, K. and Sadda, S. R.; Beckman Initiative for Macular Research Classification Committee (2013) Clinical classification of age-related macular degeneration. Ophthalmology 120, 844-851. https://doi.org/10.1016/j.ophtha.2012.10.036
  6. Fontaine, V., Monteiro, E., Fournie, M., Brazhnikova, E., Boumedine, T., Vidal, C., Balducci, C., Guibout, L., Latil, M., Dilda, P. J., Veillet, S., Sahel, J. A., Lafont, R. and Camelo, S. (2020) Systemic administration of the di-apocarotenoid norbixin (BIO201) is neuroprotective, preserves photoreceptor function and inhibits A2E and lipofuscin accumulation in animal models of age-related macular degeneration and Stargardt disease. Aging (Albany N.Y.) 12, 6151-6171. https://doi.org/10.18632/aging.103014
  7. Holz, F. G., Bellmann, C., Margaritidis, M., Schutt, F., Otto, T. P. and Volcker, H. E. (1999) Patterns of increased in vivo fundus autofluorescence in the junctional zone of geographic atrophy of the retinal pigment epithelium associated with age-related macular degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 237, 145-152. https://doi.org/10.1007/s004170050209
  8. Holz, F. G., Strauss, E. C., Schmitz-Valckenberg, S. and van Lookeren Campagne, M. (2014) Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology 121, 1079-1091. https://doi.org/10.1016/j.ophtha.2013.11.023
  9. Jager, R. D., Mieler, W. F. and Miller, J. W. (2008) Age-related macular degeneration. N. Engl. J. Med. 358, 2606-2617. https://doi.org/10.1056/NEJMra0801537
  10. Jeong, S. Y., Gu, X. and Jeong, K. W. (2019) Photoactivation of Nretinylidene-N-retinylethanolamine compromises autophagy in retinal pigmented epithelial cells. Food Chem. Toxicol. 131, 110555. https://doi.org/10.1016/j.fct.2019.06.002
  11. Jin, H. L., Choung, S. Y. and Jeong, K. W. (2017) Protective mechanisms of polyphenol-enriched fraction of Vaccinium uliginosum L. Against blue light-induced cell death of human retinal pigmented epithelial cells. J. Funct. Foods 39, 28-36. https://doi.org/10.1016/j.jff.2017.10.009
  12. Kim, J., Jin, H. L., Jang, D. S., Jeong, K. W. and Choung, S. Y. (2018a) Hyperoside (quercetin-3-O-β-D-galactopyranoside) protects A2E-laden retinal pigmented epithelium cells against UVA and blue light-induced apoptosis in vitro and in vivo. J. Funct. Foods 40, 426-437. https://doi.org/10.1016/j.jff.2017.11.021
  13. Kim, J., Jin, H. L., Jang, D. S., Jeong, K. W. and Choung, S. Y. (2018b) Quercetin-3-O-alpha-l-arabinopyranoside protects against retinal cell death via blue light-induced damage in human RPE cells and Balb-c mice. Food Funct. 9, 2171-2183. https://doi.org/10.1039/C7FO01958K
  14. Kuleshov, M. V., Jones, M. R., Rouillard, A. D., Fernandez, N. F., Duan, Q., Wang, Z., Koplev, S., Jenkins, S. L., Jagodnik, K. M., Lachmann, A., McDermott, M. G., Monteiro, C. D., Gundersen, G. W. and Ma'ayan, A. (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44, W90-W97.
  15. Lee, B. L., Kang, J. H., Kim, H. M., Jeong, S. H., Jang, D. S., Jang, Y. P. and Choung, S. Y. (2016) Polyphenol-enriched Vaccinium uliginosum L. fractions reduce retinal damage induced by blue light in A2E-laden ARPE19 cell cultures and mice. Nutr. Res. 36, 1402-1414. https://doi.org/10.1016/j.nutres.2016.11.008
  16. Lin, C. H., Wu, M. R., Huang, W. J., Chow, D. S., Hsiao, G. and Cheng, Y. W. (2019) Low-luminance blue light-enhanced phototoxicity in A2E-laden RPE cell cultures and rats. Int. J. Mol. Sci. 20, 1799. https://doi.org/10.3390/ijms20071799
  17. Marie, M., Bigot, K., Angebault, C., Barrau, C., Gondouin, P., Pagan, D., Fouquet, S., Villette, T., Sahel, J. A., Lenaers, G. and Picaud, S. (2018) Light action spectrum on oxidative stress and mitochondrial damage in A2E-loaded retinal pigment epithelium cells. Cell Death Dis. 9, 287. https://doi.org/10.1038/s41419-018-0331-5
  18. Pham, T. N. M., Shin, C. Y., Park, S. H., Lee, T. H., Ryu, H. Y., Kim, S. B., Auh, K. and Jeong, K. W. (2021) Solanum melongena L. extract protects retinal pigment epithelial cells from blue light-induced phototoxicity in in vitro and in vivo models. Nutrients 13, 359. https://doi.org/10.3390/nu13020359
  19. Radeke, M. J., Peterson, K. E., Johnson, L. V. and Anderson, D. H. (2007) Disease susceptibility of the human macula: differential gene transcription in the retinal pigmented epithelium/choroid. Exp. Eye Res. 85, 366-380. https://doi.org/10.1016/j.exer.2007.05.006
  20. Rickman, C. B., Farsiu, S., Toth, C. A. and Klingeborn, M. (2013) Dry age-related macular degeneration: mechanisms, therapeutic targets, and imaging. Invest. Ophthalmol. Vis. Sci. 54, ORSF68- ORSF80. https://doi.org/10.1167/iovs.13-12757
  21. Ul-Haq, A., Jin, M. L., Jeong, K. W., Kim, H. M. and Chun, K. H. (2019) Isolation of MLL1 inhibitory RNA aptamers. Biomol. Ther. (Seoul) 27, 201-209. https://doi.org/10.4062/biomolther.2018.157
  22. Wielgus, A., Collier, R., Martin, E., Lih, F., Tomer, K., Chignell, C. and Roberts, J. (2010) Blue light induced A2E oxidation in rat eyes - experimental animal model of dry AMD. Photochem. Photobiol. Sci. 9, 1505-1512. https://doi.org/10.1039/c0pp00133c
  23. Winkler, T. W., Grassmann, F., Brandl, C., Kiel, C., Gunther, F., Strunz, T., Weidner, L., Zimmermann, M. E., Korb, C. A., Poplawski, A., Schuster, A. K., Muller-Nurasyid, M., Peters, A., Rauscher, F. G., Elze, T., Horn, K., Scholz, M., Canadas-Garre, M., McKnight, A. J., Quinn, N., Hogg, R. E., Kuchenhoff, H., Heid, I. M., Stark, K. J. and Weber, B. H. F. (2020) Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease. BMC Med. Genomics 13, 120. https://doi.org/10.1186/s12920-020-00760-7
  24. Yakovleva, M. A., Radchenko, A. S., Feldman, T. B., Kostyukov, A. A., Arbukhanova, P. M., Borzenok, S. A., Kuzmin, V. A. and Ostrovsky, M. A. (2020) Fluorescence characteristics of lipofuscin fluorophores from human retinal pigment epithelium. Photochem. Photobiol. Sci. 19, 920-930. https://doi.org/10.1039/C9PP00406H
  25. Yang, L., Jin, M., Park, S. J., Seo, S. Y. and Jeong, K. W. (2020) SET-D1A promotes proliferation of castration-resistant prostate cancer cells via FOXM1 transcription. Cancers (Basel) 12, 1736. https://doi.org/10.3390/cancers12071736