Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy
Neovascularization Is Attenuated With Aldosterone Synthase Inhibition in Rats With Retinopathy
复制标题
DOI：
10.1161/hypertensionaha.111.188136
复制
发表时间：
2012-03-01
期刊：
影响因子：
8.3
通讯作者：
Wilkinson-Berka, Jennifer L.
中科院分区：
文献类型：
--
作者：
Deliyanti, Devy;Miller, Antonia G.;Wilkinson-Berka, Jennifer L.
新生血管是早产儿视网膜病变和糖尿病视网膜病变的标志性特征。1型血管紧张素受体阻滞剂可减少实验性早产儿视网膜病变（称为氧诱导性视网膜病变（OIR））中的新生血管形成。我们在OIR中研究了用醛固酮合成酶抑制剂FAD 286抑制醛固酮是否能像血管紧张素受体阻滞剂（缬沙坦）一样有效地减少新生血管形成。在新生Sprague-Dawley大鼠中诱导OIR，并用FAD 286（30 mg/kg/天）、缬沙坦（10 mg/kg/天）或FAD 286+缬沙坦处理它们。在参与新生血管形成的视网膜细胞（原代内皮细胞、周细胞、小神经胶质细胞、神经节细胞和神经胶质细胞）中评价了醛固酮合酶、盐皮质激素受体和11 β-羟基类固醇脱氢酶2的细胞来源。在OIR中，FAD 286分别减少了89%和67%的新生血管和新生血管簇，并使血管内皮生长因子mRNA（1.74倍）和蛋白质（4.74倍）的增加正常化，与缬沙坦和FAD 286+缬沙坦一样有效。在视网膜中，FAD 286降低了醛固酮合成酶mRNA，但缬沙坦没有降低。在小胶质细胞、神经节细胞和神经胶质细胞中检测到醛固酮合成酶，而盐皮质激素受体和11 β-羟基类固醇脱氢酶2存在于所有研究的细胞类型中。鉴于小胶质细胞中醛固酮合酶的位置及其对OIR中视网膜炎症和新生血管形成的贡献，研究了FAD 286对小胶质细胞密度的影响。在OIR中小胶质细胞密度（离子钙结合衔接蛋白1免疫标记）的增加随着所有处理而减少。在OIR中，FAD 286降低了肿瘤坏死因子-α、细胞间粘附分子1、血管细胞粘附分子1和单核细胞趋化分子1的mRNA的增加。这些发现表明，醛固酮抑制可能是一种潜在的治疗视网膜新生血管。（高血压。2012; 59：607-613.）。在线补充资料
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 11 beta-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 11 beta-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-alpha, 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. (Hypertension. 2012; 59: 607-613.). Online Data Supplement