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Francine F Behar-Cohen, Marylin Der Nigoghossian, Rinath Levy, Min Zhao, Charlotte Andrieu-Soler; Mechanism of action of mineralocorticoid receptor in the retina: evidences from transcriptomic analyses. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
After showing that the retina is a mineralosensitive tissue responding to mineralocorticoid receptor (MR) by choroid dilation through SK3 (KCA2.3) overexpression in the choroidal vessels, we have proposed mineralocorticoid receptor antagonists (MRA) to reduce subretinal fluid in non-resolutive central serous chorioretinopathy (CSCR). The exact mechanisms of action of MRA on the neuroretina under physiologic or pathogenic conditions have not been fully explored. Our aim was to analyze the transcriptional effects of aldosterone or spironolactone on the normal rat retina.
Adult female Lewis rats were sacrificed 24h after intravitreous injections (5µl) of either aldosterone, spironolactone or the control vehicle (0,9% NaCl, 0,01% ethanol). Total RNA was isolated from the neuroretinas. 3 per condition were prepared for RNA-sequencing. Sequences were aligned to the rat genome. The regulated genes evidenced by RNA-sequencing were further validated by quantitative PCR using fluorescent DNA binding dye detection. The HPRT1 was used as an internal control.
31 genes were significantly regulated by aldosterone, most of them being down-regulated and 2 being up-regulated. Seven genes (22%) contribute to angiogenesis (Col4A3, Col4A5, Col4A2, Col1A2, Col9A2, Wls, Metml), 8 genes (25%) encode for proteins involved in ion and water transport and edema. 30% of the regulated genes were enriched in the human macula. Lcn2 was up-regulated by aldosterone as expected.After spironolactone injection, 127 genes were regulated, 13 were up-regulated and 114 were down-regulated. Spironolactone regulated crystalline family genes, Scl family, aquaporin and ocular specific genes. Lcn2 and galectin-associated protein were down-regulated as expected.
MR agonist and antagonist regulate specific and different genes. Expected MR targets were found and new genes were identified, particularly those involved in angiogenesis, ion and water channel transport, osmoregulator and inflammation and oxidative stress, supposing anti-edematous effect of MRA independently from VEGF pathway. In addition to CSCR, MRA could have other applications taking into account that inflammation/ angiogenesis/ edema gene expression pathways are regulated in the neuroretina.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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