Abstract 68: Mineralocorticoid Receptor Activation Leads to Ocular Choroidal Vessels Dilation and Leakage in Rats and Human Central Serous Chorioretinopathy

Abstract

We have shown that several cell types of the rat retina express the mineralocorticoid receptor (MR) and the MR-protecting enzyme HSD2 (Zhao et al, FASEB J 2010, 24:3405), raising the question of the role of the MR in normal and diseased retina. We now questionned the role of MR in the choroid vessels lying in the outermost posterior part of the eye. Intravitreous injection of the MR ligand aldosterone in rat eye induced, 24 hrs later, dilation of choroid vessels and fluid leakage, through specific MR activation. Corticosterone (at high doses, not low doses) elicited the same effect, presumably via MR occupancy. We identified an underlying mechanism: aldosterone up-regulates the endothelial vasodilatory potassium channel KCa2.3; its blockade(by intravitreous apamine) prevents aldosterone-induced thickening. We seached whether human retinal diseases may recapitulate some of the features of MR overactivation. Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease affecting young stressed men, with unknown pathogeny and no validated treatment. Subretinal fluid accumulation originates from dilation and leakage of choroid vessels underneath the retina. Recurrence or chronic evolution may occur, leading eventually to vision loss. Based on aggravation of CSCR by glucocorticoids , on identification of systemic and/or locoregional glucocorticoids as known risk factors, and on the recognized MR affinity for glucocorticoids, we hypothesized that inappropriate/excessive occupancy of the MR by glucocorticoids may occur in the choroid of CSCR patients. Four patients with chronic non-resolved CSCR (and reduction of visual acuity) received low doses of oral eplerenone for 5 weeks. Retinal detachment and choroidal vasodilation were rapidly (1- 2 weeks) resolved; this impressive recovery was associated with improved visual acuity. The benefit was maintained after eplerenone withdrawal. Controlled clinical trials are now required to assess this novel therapeutic approach. In conclusion, our results identify MR signaling as a novel pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, leading to proposal of short-term MR blockade to reverse the choroid vasculopathy and improve vision.