Role of light in the regulation of ocular corticosteroids and its involvement in myopic staphyloma

Abstract

Purpose : The retinal pigment epithelium (RPE) might be an important target cell type in the development of posterior staphyloma as the mutation of megalin (a multiligand receptor) in RPE cells induces high myopia (HM) and staphyloma. Staphyloma results from elongation of the eye, thinning of the choroid, and a posterior protrusion that stretches the retina and the RPE/choroid/sclera complex. In addition to genetic factors, environmental factors and particularly light exposure is recognized as a major factor for HM development. There is an interaction between light exposure, circadian cycle and the concentration of hormones, such as corticosteroids but the exact role of light and corticoids on the expression of genes involved in HM and staphyloma has not been analyzed in RPE cells.
The aim of this work was to analyze the expression of genes involved in HM and staphyloma in human RPE cells derived from iPSc in response to light or corticoids exposure.

Methods : Human iPSC-derived RPE (iRPE) cells were treated with aldosterone, cortisol and cortisol + RU-486 for RNA-Seq transcriptome analysis. In a second experiment, iRPE cells were exposed at 180j/cm² light dose at 8:00 a.m. during 5 consecutive days to white light (2700K), blue (454nm) or red (631nm) light. On day 5, iRPE cells were collected for RNA extraction at 9:00 a.m., 12:00 p.m. and 8:00 p.m. Circadian clock (PER1, PER2, PER3, CLOCK, BMAL1, CRY1, CRY2), tissue remodeling- (MMP2, TIMP2, ABCA4, COL1A1) corticosteroids- (NR3C2, NR3C1, HSD11B2) and connexin-related (GJD2) genes expression were assessed by RT-qPCR.

Results : Treatment of iRPE cells with corticosteroids induced changes in gene expression of PER1, ABCA4, COL1A1, GJD2 and DKK1. These genes have been found to be associated with the development of HP. Moreover, only exposure to blue light induced in iRPE cells an overexpression of the glucocorticoid receptor (NR3C1) and a decrease in GJD2 transcripts, while the expression of most of genes of interest was differentially regulated in all lighting conditions when compared to unexposed control cells.

Conclusions : Data suggest a biological crosstalk between corticosteroids mechanisms of action and detrimental alteration of the circadian rhythm by inappropriate light exposure, resulting in the activation of molecular events implicated in posterior staphyloma pathogenesis in highly myopic individuals.

This is a 2021 ARVO Annual Meeting abstract.