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Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice

Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator 1-α...

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Autores principales: Blasiak, Janusz, Koskela, Ali, Pawlowska, Elzbieta, Liukkonen, Mikko, Ruuth, Johanna, Toropainen, Elisa, Hyttinen, Juha M. T., Viiri, Johanna, Eriksson, John E., Xu, Heping, Chen, Mei, Felszeghy, Szabolcs, Kaarniranta, Kai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915526/
https://www.ncbi.nlm.nih.gov/pubmed/33567500
http://dx.doi.org/10.3390/ijms22041684
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author Blasiak, Janusz
Koskela, Ali
Pawlowska, Elzbieta
Liukkonen, Mikko
Ruuth, Johanna
Toropainen, Elisa
Hyttinen, Juha M. T.
Viiri, Johanna
Eriksson, John E.
Xu, Heping
Chen, Mei
Felszeghy, Szabolcs
Kaarniranta, Kai
author_facet Blasiak, Janusz
Koskela, Ali
Pawlowska, Elzbieta
Liukkonen, Mikko
Ruuth, Johanna
Toropainen, Elisa
Hyttinen, Juha M. T.
Viiri, Johanna
Eriksson, John E.
Xu, Heping
Chen, Mei
Felszeghy, Szabolcs
Kaarniranta, Kai
author_sort Blasiak, Janusz
collection PubMed
description Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) genes caused AMD-like pathological phenotypes in mice. In the present work, we show hijacked epithelial-mesenchymal transition (EMT) due to the common loss of PGC-1α and NFE2L2 (double knock-out, dKO) genes in aged animals. The implanted area was assessed by histology, immunohistochemistry and transmission electron microscopy. Confocal microscopy revealed altered regions in the filamentous actin ring. This contrasted with hexagonal RPE morphology in wild-type mice. The ultrastructural RPE features here illustrated loss of apical microvilli, alteration of cell-cell contact, loss of basal in-folding with deposits on Bruch’s membrane, and excessive lipofuscin deposition in dKO samples. We also found the expression of epithelial-mesenchymal transition transcription factors, such as Snail, Slug, collagen 1, vimentin and OB-cadherin, to be significantly different in dKO RPEs. An increased immunoreactivity of senescence markers p16, DEC1 and HMGB1 was also noted. These findings suggest that EMT and senescence pathways may intersect in the retinas of dKO mice. Both processes can be activated by damage to the RPE, which may be caused by increased oxidative stress resulting from the absence of NFE2L2 and PGC-1α genes, important for antioxidant defense. This dKO model may provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease.
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spelling pubmed-79155262021-03-01 Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice Blasiak, Janusz Koskela, Ali Pawlowska, Elzbieta Liukkonen, Mikko Ruuth, Johanna Toropainen, Elisa Hyttinen, Juha M. T. Viiri, Johanna Eriksson, John E. Xu, Heping Chen, Mei Felszeghy, Szabolcs Kaarniranta, Kai Int J Mol Sci Article Age-related macular degeneration (AMD) is the most prevalent form of irreversible blindness worldwide in the elderly population. In our previous studies, we found that deficiencies in the nuclear factor, erythroid 2 like 2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) genes caused AMD-like pathological phenotypes in mice. In the present work, we show hijacked epithelial-mesenchymal transition (EMT) due to the common loss of PGC-1α and NFE2L2 (double knock-out, dKO) genes in aged animals. The implanted area was assessed by histology, immunohistochemistry and transmission electron microscopy. Confocal microscopy revealed altered regions in the filamentous actin ring. This contrasted with hexagonal RPE morphology in wild-type mice. The ultrastructural RPE features here illustrated loss of apical microvilli, alteration of cell-cell contact, loss of basal in-folding with deposits on Bruch’s membrane, and excessive lipofuscin deposition in dKO samples. We also found the expression of epithelial-mesenchymal transition transcription factors, such as Snail, Slug, collagen 1, vimentin and OB-cadherin, to be significantly different in dKO RPEs. An increased immunoreactivity of senescence markers p16, DEC1 and HMGB1 was also noted. These findings suggest that EMT and senescence pathways may intersect in the retinas of dKO mice. Both processes can be activated by damage to the RPE, which may be caused by increased oxidative stress resulting from the absence of NFE2L2 and PGC-1α genes, important for antioxidant defense. This dKO model may provide useful tools for studying AMD pathogenesis and evaluating novel therapies for this disease. MDPI 2021-02-08 /pmc/articles/PMC7915526/ /pubmed/33567500 http://dx.doi.org/10.3390/ijms22041684 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Blasiak, Janusz
Koskela, Ali
Pawlowska, Elzbieta
Liukkonen, Mikko
Ruuth, Johanna
Toropainen, Elisa
Hyttinen, Juha M. T.
Viiri, Johanna
Eriksson, John E.
Xu, Heping
Chen, Mei
Felszeghy, Szabolcs
Kaarniranta, Kai
Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice
title Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice
title_full Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice
title_fullStr Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice
title_full_unstemmed Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice
title_short Epithelial-Mesenchymal Transition and Senescence in the Retinal Pigment Epithelium of NFE2L2/PGC-1α Double Knock-Out Mice
title_sort epithelial-mesenchymal transition and senescence in the retinal pigment epithelium of nfe2l2/pgc-1α double knock-out mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915526/
https://www.ncbi.nlm.nih.gov/pubmed/33567500
http://dx.doi.org/10.3390/ijms22041684
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