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Francine F Behar-Cohen, Rocio Herrero-Vanrell, Fréderic Jaisser, Rinath Levy, Alejandro Arboleda, XinXin Li, Min Zhao; The multiple effects of mineralocorticoid antagonists for the treatment of retinal diseases. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4629.
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Both gluco and mineralocorticoid receptors (MR) are expressed in retinal cells, endothelial cells from retinal and choroidal cells and in retinal pigment epithelial cells [Zhao M et al FASEB J. 2010]. In the normal retina, MR activation by aldosterone induces retinal edema and choroidal vasodilation, providing the basis for mineralocorticoid antagonists (MRA) use in central serous chorioretinopathy [Zhao M et al J Clin Invest. 2012].But the role of MR in pathologic retinal conditions is unclear. Our purpose was to evaluate the role of MR and its antagonism in diabetic retinopathy and choroidal neovascularization in rodents.
The expression of MR was evaluated in the retina and RPE/ choroid in three animal models of diabetes (type 1 and type 2) and in laser-induced choroidal neovascularization. Aldosterone was measured in the aqueous humor and vitreous of diabetic patients. Marker of MR activation (Ngal/ lipocalin 2) levels were measured in the vitreous of diabetic patients and in the retina of diabetic rodents. The effect of spironolactone on retinal thickness was evaluated in one-year old GK rats.The effect of MR blockade was assessed in laser-induced choroidal neovascularization (CNV) either with pharmacologic inhibition (local and systemic) or by transgenic mice constructions ( MR flox/flox/Tie2 Cre/+, MR flox/floxLysM Cre/+)..
In three rodent models of diabetes, MR is over-expressed in the retina and markers of MR activation are elevated . In diabetic patients same markers are elevated in the ocular media and aldosterone is increased. Sustained release of intraocular spironolactone significantly reduced retinal thickness of one-year old GK rats.In laser-induced CNV, both pharmacologic and transgenic MR inhibition significantly reduced neovascularization in a VEGF-independent manner. MRA and anti-VEGF had synergystic effects.MRA significantly reduced microglial invasion and activation in the choroid.No adverse effects resulted from intraocular administration of MRA.
New mechanisms of action and new molecular targets of MRA have been identified in the retina.MRA seems promising drugs not only in the tretament of CSCR but also in other retinal diseases associated with macular edema of diverse orignis.Preliminary results in patients support this hypothesis but clinical trials must be conducted to confirm this hypothesis.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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