Abstract
Purpose :
Glucocorticoids (GCs) pleiotropic, anti-inflammatory and anti-edematous effects have prompted the development of exogenous synthetic glucocorticoids. These are extremely used in the treatment of retinal diseases and optimized for improved glucocorticoid receptor (GR) pathway activation over mineralocorticoid receptor (MR). While GR/MR balance is essential to ensure a proper function of GCs signaling, MR pathway activation can be pathogenic and have shown to contribute to edematous, neovascular and inflammatory processes, but the exact mechanisms remains to be analyzed.
Methods :
The aim is to study the consequences of abnormal MR activation, in two different models of MR pathway activation through either receptor overexpression (animals overexpressing the human MR under the control of P1 promoter, P1.hMR transgenic mice and rats) or through aldosterone increase in a nephrectomy/aldosterone/salt mouse model (NAS mice). For both models, histological studies allowed to evaluate the structure of the posterior segment and the choroidal innervation. In addition, transcriptomics analysis of the choroid/RPE complex were performed to highlight the underlying mechanisms of the pathophysiology.
Results :
P1.hMR animals display several signs of chorioretinopathy, including anomalies in the photoreceptor outer segments, the RPE and the choroid. Immunostaining in P1.hMR rats reveals that both IBA1+ choroidal immune cells and retinal microglia display activated morphology, indicating an inflammation state in both structures. Moreover, the choroidal innervation is significantly increased while showing different signs of neuropathy. Transcriptomics analysis highlight (neuro)inflammatory processes and choroidal innervation deregulation, while GR/MR balance is in favor of MR signaling. NAS mice show aggravated chorioretinopathy and neuropathy compared to P1.hMR, associated with transcriptomics markers of (neuro)inflammation and downregulation of GR.
Conclusions :
While MR is strongly associated with eye diseases such as CSCR, overexpressing the MR or chronically increase its ligand leads to chorioretinopathy and choroidal neuropathy, coinciding with a GR/MR balance in favor of MR signaling. If the exact underlying mechanisms can differ whether the receptor or the ligand are affected, (neuro-)inflammation and neurogenic inflammation could constitute common processes in the etiology of human pathophysiology.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.