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Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium

Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier...

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Autores principales: Canonica, Jérémie, Zhao, Min, Favez, Tatiana, Gelizé, Emmanuelle, Jonet, Laurent, Kowalczuk, Laura, Guegan, Justine, Le Menuet, Damien, Viengchareun, Say, Lombès, Marc, Pussard, Eric, Arsenijevic, Yvan, Behar-Cohen, Francine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431771/
https://www.ncbi.nlm.nih.gov/pubmed/34502527
http://dx.doi.org/10.3390/ijms22179618
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author Canonica, Jérémie
Zhao, Min
Favez, Tatiana
Gelizé, Emmanuelle
Jonet, Laurent
Kowalczuk, Laura
Guegan, Justine
Le Menuet, Damien
Viengchareun, Say
Lombès, Marc
Pussard, Eric
Arsenijevic, Yvan
Behar-Cohen, Francine
author_facet Canonica, Jérémie
Zhao, Min
Favez, Tatiana
Gelizé, Emmanuelle
Jonet, Laurent
Kowalczuk, Laura
Guegan, Justine
Le Menuet, Damien
Viengchareun, Say
Lombès, Marc
Pussard, Eric
Arsenijevic, Yvan
Behar-Cohen, Francine
author_sort Canonica, Jérémie
collection PubMed
description Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone—an MR-specific agonist, or cortisol or cortisol + RU486—a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling (CNN1, MGP, AMTN), epithelial–mesenchymal transition, RPE cell proliferation and migration (ITGB3, PLAUR and FOSL1) and immune balance (TNFSF18 and PTX3). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology.
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spelling pubmed-84317712021-09-11 Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium Canonica, Jérémie Zhao, Min Favez, Tatiana Gelizé, Emmanuelle Jonet, Laurent Kowalczuk, Laura Guegan, Justine Le Menuet, Damien Viengchareun, Say Lombès, Marc Pussard, Eric Arsenijevic, Yvan Behar-Cohen, Francine Int J Mol Sci Article Glucocorticoids are amongst the most used drugs to treat retinal diseases of various origins. Yet, the transcriptional regulations induced by glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation in retinal pigment epithelium cells (RPE) that form the outer blood–retina barrier are unknown. Levels of endogenous corticoids, ligands for MR and GR, were measured in human ocular media. Human RPE cells derived from induced pluripotent stem cells (iRPE) were used to analyze the pan-transcriptional regulations induced by aldosterone—an MR-specific agonist, or cortisol or cortisol + RU486—a GR antagonist. The retinal phenotype of transgenic mice that overexpress the human MR (P1.hMR) was analyzed. In the human eye, the main ligand for GR and MR is cortisol. The iRPE cells express functional GR and MR. The subset of genes regulated by aldosterone and by cortisol + RU-486, and not by cortisol alone, mimics an imbalance toward MR activation. They are involved in extracellular matrix remodeling (CNN1, MGP, AMTN), epithelial–mesenchymal transition, RPE cell proliferation and migration (ITGB3, PLAUR and FOSL1) and immune balance (TNFSF18 and PTX3). The P1.hMR mice showed choroidal vasodilation, focal alteration of the RPE/choroid interface and migration of RPE cells together with RPE barrier function alteration, similar to human retinal diseases within the pachychoroid spectrum. RPE is a corticosteroid-sensitive epithelium. MR pathway activation in the RPE regulates genes involved in barrier function, extracellular matrix, neural regulation and epithelial differentiation, which could contribute to retinal pathology. MDPI 2021-09-05 /pmc/articles/PMC8431771/ /pubmed/34502527 http://dx.doi.org/10.3390/ijms22179618 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Canonica, Jérémie
Zhao, Min
Favez, Tatiana
Gelizé, Emmanuelle
Jonet, Laurent
Kowalczuk, Laura
Guegan, Justine
Le Menuet, Damien
Viengchareun, Say
Lombès, Marc
Pussard, Eric
Arsenijevic, Yvan
Behar-Cohen, Francine
Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium
title Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium
title_full Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium
title_fullStr Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium
title_full_unstemmed Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium
title_short Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium
title_sort pathogenic effects of mineralocorticoid pathway activation in retinal pigment epithelium
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431771/
https://www.ncbi.nlm.nih.gov/pubmed/34502527
http://dx.doi.org/10.3390/ijms22179618
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