Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
Hypertension. 2012 Mar;59(3):607-13. doi: 10.1161/HYPERTENSIONAHA.111.188136. Epub 2012 Jan 23.
Neovascularization is a hallmark feature of retinopathy of prematurity and diabetic retinopathy. Type 1 angiotensin receptor blockade reduces neovascularization in experimental retinopathy of prematurity, known as oxygen-induced retinopathy (OIR). We investigated in OIR whether inhibiting aldosterone with the aldosterone synthase inhibitor FAD286 reduced neovascularization as effectively as angiotensin receptor blockade (valsartan). OIR was induced in neonatal Sprague-Dawley rats, and they were treated with FAD286 (30 mg/kg per day), valsartan (10 mg/kg per day), or FAD286+valsartan. The cellular sources of aldosterone synthase, the mineralocorticoid receptor, and 11β-hydroxysteroid dehydrogenase 2 were evaluated in retinal cells involved in neovascularization (primary endothelial cells, pericytes, microglia, ganglion cells, and glia). In OIR, FAD286 reduced neovascularization and neovascular tufts by 89% and 67%, respectively, and normalized the increase in vascular endothelial growth factor mRNA (1.74-fold) and protein (4.74-fold) and was as effective as valsartan and FAD286+valsartan. In retina, aldosterone synthase mRNA was reduced with FAD286 but not valsartan. Aldosterone synthase was detected in microglia, ganglion cells, and glia, whereas mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase 2 were present in all of the cell types studied. Given the location of aldosterone synthase in microglia and their contribution to retinal inflammation and neovascularization in OIR, the effects of FAD286 on microglial density were studied. The increase in microglial density (ionized calcium binding adaptor protein 1 immunolabeling) in OIR was reduced with all of the treatments. In OIR, FAD286 reduced the increase in mRNA for tumor necrosis factor-α, intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and monocyte chemoattractant molecule 1. These findings indicate that aldosterone inhibition may be a potential treatment for retinal neovascularization.
血管新生是早产儿视网膜病变和糖尿病视网膜病变的一个显著特征。1 型血管紧张素受体阻断可减少实验性早产儿视网膜病变（氧诱导视网膜病变，OIR）中的血管新生。我们在 OIR 中研究了醛固酮合酶抑制剂 FAD286 是否能像血管紧张素受体阻断（缬沙坦）一样有效抑制醛固酮，从而减少血管新生。在新生 Sprague-Dawley 大鼠中诱导 OIR，并给予 FAD286（每天 30mg/kg）、缬沙坦（每天 10mg/kg）或 FAD286+缬沙坦治疗。评估了参与血管新生的视网膜细胞（原代内皮细胞、周细胞、小胶质细胞、神经节细胞和胶质细胞）中醛固酮合酶、盐皮质激素受体和 11β-羟类固醇脱氢酶 2 的细胞来源。在 OIR 中，FAD286 使血管新生减少 89%，血管新生簇减少 67%，并使血管内皮生长因子 mRNA（1.74 倍）和蛋白（4.74 倍）的增加正常化，与缬沙坦和 FAD286+缬沙坦一样有效。在视网膜中，FAD286 可降低醛固酮合酶 mRNA，但缬沙坦不行。在小胶质细胞、神经节细胞和胶质细胞中检测到醛固酮合酶，而盐皮质激素受体和 11β-羟类固醇脱氢酶 2 存在于所有研究的细胞类型中。鉴于醛固酮合酶在小胶质细胞中的位置及其在 OIR 中对视网膜炎症和血管新生的贡献，研究了 FAD286 对小胶质细胞密度的影响。用所有处理方法均可减少 OIR 中小胶质细胞密度（离子钙结合衔接蛋白 1 免疫标记）的增加。在 OIR 中，FAD286 降低了肿瘤坏死因子-α、细胞间黏附分子 1、血管细胞黏附分子 1 和单核细胞趋化蛋白 1 的 mRNA 增加。这些发现表明，抑制醛固酮可能是治疗视网膜血管新生的一种潜在方法。
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