Abstract
Purpose :
MS a posterior protrusion of the eyeball occurring in high myopic eyes, associates thinning of the choroid and stretch of the retina and the retinal pigment epithelium (RPE)/choroid/sclera complex. In addition to genetic factors, light exposure, is recognized as a major factor in the development of HM, but its role in MS is unknown.
The loss of function of megalin (a multiligand receptor) in RPE cells, in human and transgenic rodent, causes high myopia (HM) and MS, indicating that RPE is involved in MS. Transthyretin is a megalin ligand that regulates megalin levels and activates the intracellular cleavage, producing an intracellular domain, which is translocated to the nucleus to regulate gene expression.
The mechanisms linking megalin and RPE dysfunction and MS have not been investigated and the potential role of light on the expression of genes involved in HM and staphyloma has not been analyzed in RPE cells.
The aim of this work was to evaluate the role of megalin and of its partners in the development of PS, using retina and iPSc-derived human RPE cells (iRPE).
Methods :
Immunofluorescences were performed to characterize megalin and its partners expression and localization in human and in megalin knock-out mouse. Proteomic analyses were performed on human vitreous samples from HM patients with PS to correlate with megalin KO mouse. The effects of megalin invalidation, transthyretin and white (2700K), blue (454nm) or red (631nm) light was evaluated on iRPE, using transcriptomic and western blot analysis.
Results :
Megalin is enriched in the human macula, with clear evidence of a nuclear localization in retina and RPE cells. Transthyretin accumulates in the retina of megalin ko mice. Down regulation of megalin in iRPEs induces results in BMP4 down-regulation. Transthyretin stimulated megalin and BMP4 synthesis in iRPE. Megalin expression was an enhanced by red light exposure in iRPE cells.
Conclusions :
In iRPE cells, megalin acts as a transcription factor, regulated by red light. It controls the expression of genes involved in PS development. In human, megalin is enriched in nuclei of macular cells.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.