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Open AccessArticle

Resveratrol as Inducer of Autophagy, Pro-Survival, and Anti-Inflammatory Stimuli in Cultured Human RPE Cells

1
Department of Ophthalmology, Center for Eye Research, Oslo University Hospital and University of Oslo, 0450 Oslo, Norway
2
Department of Ophthalmology, Faculty of Medicine, University of Szeged, 6720 Szeged, Hungary
3
Department of Ophthalmology, Justus-Liebig-University Giessen, Eye Clinic, University Hospital Giessen, 35390 Giessen, Germany
4
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland and Kuopio University Hospital, 70210 Kuopio, Finland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 813; https://doi.org/10.3390/ijms21030813
Received: 28 October 2019 / Revised: 31 December 2019 / Accepted: 7 January 2020 / Published: 27 January 2020
(This article belongs to the Special Issue Molecular Biology of Age-Related Macular Degeneration (AMD) 2.0)
Purpose: To investigate the mechanism by which resveratrol acts upon retinal pigment epithelial (RPE) cells and to characterize its effect upon autophagy, survival, and inflammation, with consequent implications to treatment for age-related macular degeneration (AMD). Methods: Cultured ARPE-19 cells were exposed to 10 and 50 μM resveratrol. Cell survival/death was determined by annexin-FITC/propidium iodide using flow cytometry, while autophagy was studied by detecting autophagic vacuoles formation (acridine orange and transmission electron microscopy), as well as LC3II/I ratio and p62 expression by Western blot. In addition, time-lapse confocal microscopy of a pDENDRA-LC3 expression vector was performed to detect autophagy in transfected ARPE-19 cells under the different treatment conditions. Inhibition of proteasomal and autophagy-lysosomal fusion was carried out by MG-132 and chloroquine, respectively, while induction of autophagy was achieved by rapamycin treatment. Detection of secreted cytokines by ARPE-19 cells using Human XL Cytokine Array was performed under oxidative stress (H2O2) and resveratrol treatments, respectively. Results: Resveratrol induced autophagy in ARPE-19 cells as determined by augmented presence of autophagic vacuoles, increased LC3II/I ratio and decreased p62 expression, as well as time-lapse confocal microscopy using pDENDRA-LC3 expression vector. Resveratrol acted similarly to proteasomal inhibition and downstream of mammalian target of rapamycin (mTOR), since upstream inhibition of autophagy by 3-methyladenine could not inhibit autophagy in ARPE-19 cells. Co-treatmeant by rapamycin and/or proteasome inhibition showed no additive effect upon autophagy induction. ARPE-19 cells treated by resveratrol showed lower cell death rate compared to untreated controls. Resveratrol induced a specific anti-inflammatory response in ARPE-19 cells. Conclusions: Resveratrol can induce autophagy, pro-survival, and anti-inflammatory stimuli in ARPE-19 cells, properties which could be plausible to formulate future treatment modalities for AMD. View Full-Text
Keywords: resveratrol; retinal pigment epithelium; autophagy; proteasomal inhibition; survival; inflammation; protein array; age-related macular degeneration resveratrol; retinal pigment epithelium; autophagy; proteasomal inhibition; survival; inflammation; protein array; age-related macular degeneration
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Josifovska, N.; Albert, R.; Nagymihály, R.; Lytvynchuk, L.; Moe, M.C.; Kaarniranta, K.; Veréb, Z.J.; Petrovski, G. Resveratrol as Inducer of Autophagy, Pro-Survival, and Anti-Inflammatory Stimuli in Cultured Human RPE Cells. Int. J. Mol. Sci. 2020, 21, 813.

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