Abstract
Purpose: :
Recently we identified that aldosterone has potent angiogenic and inflammatory actions in the retina, and that these occur via the mineralocorticoid receptor. The aim of this study was to determine if direct inhibition of aldosterone synthase with FAD286 reduces retinal vascular disease.
Methods: :
Oxygen-induced retinopathy (OIR) was induced in Sprague Dawley rats with exposure to 80% oxygen (22hrs/day) from postnatal days (P) 0 to 11, followed by 7 days in room air. Sham rats were always in room air. FAD286 (30mg/kg/day, sc) or its control vehicle tartaric acid (10mg/kg/day, sc) were administered from P12 to P18 to either OIR or sham rats (N=8 to 10 rats/group). Pathological angiogenesis in the inner retina and vitreous was assessed in paraffin sections, and by counting neovascular tufts in isolectin stained retinal wholemounts. The under-developed avascular region of the peripheral retina that develops in OIR was quantitated using ImageJ software (NIH). Vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) were measured in retina by real time PCR. The expression of NOX4, a subunit of NADPH oxidase that is implicated in aldosterone-mediated events, was also evaluated in retina with real-time PCR.
Results: :
In OIR, pathological angiogenesis (22.43±1.56 blood vessels/field) was increased compared to shams (12.91±0.38, P<0.01), and was normalised with FAD286 (14.29±0.58, P<0.01). Retinal neovascular tufts were increased 7.8-fold in OIR compared to sham control. In OIR, FAD286 reduced neovascular tufts, although not to sham levels. In OIR, the retinal avascular area was increased (8.94±2.42% of total retina) compared to shams (0.65±0.11%), and was unaffected by FAD286 (8.19±1.10%). In OIR, retinal VEGF, ICAM-1 and NOX4 mRNA levels were increased compared to sham controls. In OIR, FAD286 reduced the gene expression of VEGF, ICAM-1 and NOX4 in retina. In sham rats, FAD286 had no effect on blood vessel growth or the expression of VEGF, ICAM-1 or NOX4 in retina.
Conclusions: :
FAD286 has potent effects in OIR, reducing pathological angiogenesis, but does not restore revascularization of the peripheral retina. Aldosterone’s ability to influence retinal vasculopathy has implications for future studies aimed at improving treatments for retinal vascular diseases that involve the renin-angiotensin-aldosterone system.
Keywords: retinopathy of prematurity • inflammation • retinal neovascularization