Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy
Min Zhao, … , Frédéric Jaisser, Francine Behar-Cohen
Min Zhao, … , Frédéric Jaisser, Francine Behar-Cohen
Published June 11, 2012
Citation Information: J Clin Invest. 2012;122(7):2672-2679. https://doi.org/10.1172/JCI61427.
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Research Article Ophthalmology

Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

Abstract

Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. In CSCR, dilation and leakage of choroid vessels underneath the retina cause subretinal fluid accumulation and retinal detachment. Because glucocorticoids induce and aggravate CSCR and are known to bind to the mineralocorticoid receptor (MR), CSCR may be related to inappropriate MR activation. Our aim was to assess the effect of MR activation on rat choroidal vasculature and translate the results to CSCR patients. Intravitreous injection of the glucocorticoid corticosterone in rat eyes induced choroidal enlargement. Aldosterone, a specific MR activator, elicited the same effect, producing choroid vessel dilation -and leakage. We identified an underlying mechanism of this effect: aldosterone upregulated the endothelial vasodilatory K channel KCa2.3. Its blockade prevented aldosterone-induced thickening. To translate these findings, we treated 2 patients with chronic nonresolved CSCR with oral eplerenone, a specific MR antagonist, for 5 weeks, and observed impressive and rapid resolution of retinal detachment and choroidal vasodilation as well as improved visual acuity. The benefit was maintained 5 months after eplerenone withdrawal. Our results identify MR signaling as a pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, which suggests that blockade of MR could be used therapeutically to reverse choroid vasculopathy.

Authors

Min Zhao, Isabelle Célérier, Elodie Bousquet, Jean-Claude Jeanny, Laurent Jonet, Michèle Savoldelli, Olivier Offret, Antoine Curan, Nicolette Farman, Frédéric Jaisser, Francine Behar-Cohen

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Figure 1

Induction of choroidal thickening by MR activation in rat eyes.

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Induction of choroidal thickening by MR activation in rat eyes. (A) In v...
(A) In vivo OCT scans taken in the same region of the retina before and 24 hours after IVT of high-dose corticosterone (10 μM). Thickness of the choroid (arrows) was increased by corticosterone and associated with choroid vessel dilation (stars). Aldosterone (20 nM) also enhanced choroidal thickness and vasodilation. Scale bars: 200 μm. (B) Historesine sections illustrating increased choroidal thickness 24 hours after 10 μM corticosterone or 20 nM aldosterone compared with vehicle-injected eyes (NaCl; 0.9% added with 0.01% ethanol). Choriocapillaries (Cc) and choroid veins (CV) were dilated in corticosterone- and aldosterone-injected eyes. Arrowheads delineate the limit of the choroid and the sclera. ONL, outer nuclear layer; Chor, choroid. Scale bar: 25 μm. (C) Aldosterone-induced choroidal thickening occurred all along the retina (measured on serial photographs), from the optic nerve to the periphery. Values from aldosterone-treated (Aldo) eyes were higher than those of vehicle-injected (NaCl) eyes (n = 12–14 per condition). P < 0.001, vehicle vs. aldosterone, 2-way ANOVA. (D) Quantification of choroidal thickness measured on historesine sections. Aldosterone (20 nM) induced a significant increase in choroidal thickness compared with control vehicle-injected eyes; this was significantly inhibited by coinjection of aldosterone with 500-fold excess of a specific MR antagonist, but not a specific GR antagonist (n = 4–5 per condition). *P < 0.05, ***P < 0.001.