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.

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…However the microcirculation plays a major role in tissue pathology (Granger et al, 2010). There is a longitudinal gradient of expression of MR, with higher expression in large arteries (Lombes et al, 1992), but MR is also expressed in arterioles and capillaries (DeLano and Schmid-Schonbein, 2004;Zhao et al, 2012), although to a lower extent, and perhaps essentially only in pathologic situations. Moreover, MR expression may depend on the precise location of the vessels within an organ (for example, in the renal glomerulus afferent versus efferent arteries or peritubular capillaries).…”

“…Recent reports have demonstrated that the retina is a target tissue for mineralocorticoids, with specific involvement in eye pathology (Wilkinson-Berka et al, 2012;Zhao et al, 2012). Whether MR antagonists may exert beneficial effects in retinal diseases is a novel concept in ophthalmology.…”

Potential Side-Effects of CSC Systemic Approach

“…Gynecomastia is a frequent side-effect (10%) given its antiandrogenic effect, thus leading to increased free estradiol and total estradiol [3][4][5][6].…”

“…Its etiopathogenesis remains uncertain, with a variety of genetic and environmental factors possibly involved [1,2]. Among these, the role of steroids has arisen as a potential therapeutic target with the use of mineralocorticoid inhibitors like spironolactone or eplerenone [1,3].…”

Half-dose and half-fluence photodynamic therapy for central serous chorioretinopathy

“…Many treatment modalities have been investigated, including rifampin [2], finasteride [3], transpupillary thermotherapy [4], ketoconazole [5], mifepristone [6], indocyanine green-mediated laser treatment [7,8], propranolol [9], focal laser [9], intravitreal bevacizumab [10][11][12][13], and more recently eplerenone [14], all with limited success. With a list this long, chronic CSCR clearly defies easy treatment.…”