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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Format: | Article |
Language: | English |
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MDPI AG
2021-09-01
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Series: | International Journal of Molecular Sciences |
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Online Access: | https://www.mdpi.com/1422-0067/22/17/9618 |
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doaj-3eaa15dd4893453a9f19eb65f7cbc9d9 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jérémie Canonica Min Zhao Tatiana Favez Emmanuelle Gelizé Laurent Jonet Laura Kowalczuk Justine Guegan Damien Le Menuet Say Viengchareun Marc Lombès Eric Pussard Yvan Arsenijevic Francine Behar-Cohen |
spellingShingle |
Jérémie Canonica Min Zhao Tatiana Favez Emmanuelle Gelizé Laurent Jonet Laura Kowalczuk Justine Guegan Damien Le Menuet Say Viengchareun Marc Lombès Eric Pussard Yvan Arsenijevic Francine Behar-Cohen Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium International Journal of Molecular Sciences retina eye corticoids retinal pigment epithelium mineralocorticoid transcriptional regulation |
author_facet |
Jérémie Canonica Min Zhao Tatiana Favez Emmanuelle Gelizé Laurent Jonet Laura Kowalczuk Justine Guegan Damien Le Menuet Say Viengchareun Marc Lombès Eric Pussard Yvan Arsenijevic Francine Behar-Cohen |
author_sort |
Jérémie Canonica |
title |
Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment Epithelium |
title_short |
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_sort |
pathogenic effects of mineralocorticoid pathway activation in retinal pigment epithelium |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-09-01 |
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 (<i>CNN1</i>, <i>MGP</i>, <i>AMTN)</i>, epithelial–mesenchymal transition, RPE cell proliferation and migration (<i>ITGB3</i>, <i>PLAUR</i> and <i>FOSL1</i>) and immune balance (<i>TNFSF18</i> and <i>PTX3</i>). 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. |
topic |
retina eye corticoids retinal pigment epithelium mineralocorticoid transcriptional regulation |
url |
https://www.mdpi.com/1422-0067/22/17/9618 |
work_keys_str_mv |
AT jeremiecanonica pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT minzhao pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT tatianafavez pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT emmanuellegelize pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT laurentjonet pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT laurakowalczuk pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT justineguegan pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT damienlemenuet pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT sayviengchareun pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT marclombes pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT ericpussard pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT yvanarsenijevic pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium AT francinebeharcohen pathogeniceffectsofmineralocorticoidpathwayactivationinretinalpigmentepithelium |
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spelling |
doaj-3eaa15dd4893453a9f19eb65f7cbc9d92021-09-09T13:48:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-01229618961810.3390/ijms22179618Pathogenic Effects of Mineralocorticoid Pathway Activation in Retinal Pigment EpitheliumJérémie Canonica0Min Zhao1Tatiana Favez2Emmanuelle Gelizé3Laurent Jonet4Laura Kowalczuk5Justine Guegan6Damien Le Menuet7Say Viengchareun8Marc Lombès9Eric Pussard10Yvan Arsenijevic11Francine Behar-Cohen12Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Inserm, From Physiopathology of Retinal Diseases to Clinical Advances, 15 rue de l’Ecole de Médecine, 75006 Paris, FranceCentre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Inserm, From Physiopathology of Retinal Diseases to Clinical Advances, 15 rue de l’Ecole de Médecine, 75006 Paris, FranceDepartment of Ophthalmology, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, SwitzerlandCentre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Inserm, From Physiopathology of Retinal Diseases to Clinical Advances, 15 rue de l’Ecole de Médecine, 75006 Paris, FranceCentre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Inserm, From Physiopathology of Retinal Diseases to Clinical Advances, 15 rue de l’Ecole de Médecine, 75006 Paris, FranceDepartment of Ophthalmology, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, SwitzerlandInstitut du Cerveau, ICM, iCONICS, Hôpital de la Pitié-Salpêtrière, 75013 Paris, FrancePhysiologie et Physiopathologie Endocriniennes, Université Paris-Saclay, Inserm, 94276 Le Kremlin-Bicêtre, FrancePhysiologie et Physiopathologie Endocriniennes, Université Paris-Saclay, Inserm, 94276 Le Kremlin-Bicêtre, FrancePhysiologie et Physiopathologie Endocriniennes, Université Paris-Saclay, Inserm, 94276 Le Kremlin-Bicêtre, FrancePhysiologie et Physiopathologie Endocriniennes, Université Paris-Saclay, Inserm, 94276 Le Kremlin-Bicêtre, FranceDepartment of Ophthalmology, Jules Gonin Eye Hospital, Fondation Asile des Aveugles, University of Lausanne, 1004 Lausanne, SwitzerlandCentre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Inserm, From Physiopathology of Retinal Diseases to Clinical Advances, 15 rue de l’Ecole de Médecine, 75006 Paris, FranceGlucocorticoids 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 (<i>CNN1</i>, <i>MGP</i>, <i>AMTN)</i>, epithelial–mesenchymal transition, RPE cell proliferation and migration (<i>ITGB3</i>, <i>PLAUR</i> and <i>FOSL1</i>) and immune balance (<i>TNFSF18</i> and <i>PTX3</i>). 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.https://www.mdpi.com/1422-0067/22/17/9618retinaeyecorticoidsretinal pigment epitheliummineralocorticoidtranscriptional regulation |