Abstract
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.
Highlights
Retinal diseases are the most frequent causes of blindness in developed countries [1], and one of the major causes of vision loss is macular edema [2] that complicates retinal barriers’ breakdown
retinal pigment epithelium (RPE) Cells Differentiated from human induced pluripotent stem cell (hiPSC) Express RPE Characteristic Marker Genes and Exhibit High Transepithelial Resistance
We used a modified protocol described by Singh, R. and colleagues [25] to differentiate and expand in 60 days hiPSC into pure induced pluripotent stem cells (iRPE) cells [26] (Figure 1a) that display many features of a native RPE [27]
Summary
Retinal diseases are the most frequent causes of blindness in developed countries [1], and one of the major causes of vision loss is macular edema [2] that complicates retinal barriers’ breakdown. Intraocular glucocorticoids (GCs) reduce macular edema of various origins [5,6], but exogenous and even endogenous corticoids may induce paradoxical pro-edematous effects in pachychoroid-spectrum diseases including central serous chorioretinopathy (CSCR) [7], witnessing the complexity of their action on the retina. Neurosteroids produced by steroidogenesis in rat retinal ganglion cells [8] protected retinal neurons against ischemia through binding to the sigma-1 receptor [9], which regulates calcium, ion channels and oxidative stress [10]. In a human RPE cell line (ARPE-19), 17β-estradiol and dehydroepiandrosterone-sulfate protected against oxidativestress-induced DNA damages [11], demonstrating the crucial role of neurosteroids in retina and RPE maintenance. The transcriptional regulations induced in the RPE by MR and/or GR activation are unknown
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