Abstract
Purpose :
Glucocorticoids (GCs) are widely used for their anti-inflammatory and anti-edematous properties, exerting their effects via two receptors: the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). During the last decades, it has been shown that GCs signaling via MR activation constitute a triggering factor in several eye diseases such as CSCR, but the underlying mechanisms are still under investigation. The choroidal nervous system (CNS) plays a crucial role in choroidal physiology, including the control of choroidal blood flow. But the role of corticoids and more specifically of the MR pathway on choroidal innervation, has not yet been explored. The aim of this work was to explore the effect of MR pathway activation on the CNS.
Methods :
Both transgenic rats & mice over-expressing the human MR (hMR) under the ecologic promotor (P1) have been generated. First, immunohistochemistry and electron microscopy were used to characterize the CNS in WT rodents. Both anatomical (TUBB3, PGP9.5) and neurochemical (NPY, VIP, CGRP) markers were used. The CNS of transgenic animals was compared to WT and unbiased bulk transcriptomic analysis of RPE/choroid was conducted to compare transgenic P1 hMR animals with their littermate.
Results :
Histological characterization of CNS reveals a very dense and heterologous network which is strongly organized around the choroidal vasculature, including innervations from the autonomic (NPY, VIP) and sensory nervous system (CGRP). Furthermore, the CNS displays an important proximity with the choroidal immune cells and numerous fibers are noticeable within the choriocapillaris. Comparison between transgenic and WT animals reveals that MR overexpression is associated with changes in macrophage morphology, a denser nervous network, abnormal and larger nerves and typical ultrastructural signs of peripheral neuropathy. Transcriptomic analysis confirmed the deregulation of gene expression and pathways related to neuronal dysregulation, neuro-inflammation and neuropathy in transgenic animals as compared to WT.
Conclusions :
hMR-overexpression is associated with histological and transcriptomic dysregulation of the CNS. While CSCR is characterized by abnormal vasodilatation (pachyvessels) and inflammatory processes, the MR-dependent effect on the CNS could be a potential mechanism explaining the dysregulation of vessels dynamic, immune cells activity, and choriocapillaris/RPE physiology.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.