INSERM, UMRS 1138, Team 17, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, 75006, Paris, France; Department of Ophthalmology, University of Lausanne, Switzerland.
Department of Ophthalmology, Ophthalmopole, Hôpital Cochin, Assistance Publique, Hôpitaux de Paris, 75014, Paris, France; Department of Biostatistics, Hôpital Necker-EnfantsMalades, AP-HP, 75015, Paris, France.
Exp Eye Res. 2019 Oct;187:107747. doi: 10.1016/j.exer.2019.107747. Epub 2019 Aug 5.
Preclinical and clinical evidences show that aldosterone and/or mineralocorticoid receptor (MR) over-activation by glucocorticoids can be deleterious to the retina and to the retinal pigment epithelium (RPE)-choroid complex. However, the exact molecular mechanisms driving these effects remain poorly understood and pathological consequences of chronic exposure of the retina and RPE/choroid to aldosterone have not been completely explored. We aimed to decipher the transcriptomic regulation in the RPE-choroid complex in rats in response to acute intraocular aldosterone injection and to explore the consequences of systemic chronic aldosterone exposure on the morphology and the gene regulation in RPE/choroid in mice. High dose of aldosterone (100 nM) was intravitreously injected in Lewis rat eyes in order to yield an aldosterone dose able to induce a molecular response at the apical side of the RPE-choroid complex. The posterior segment morphology was evaluated in vivo using optical coherence tomography (OCT) before and 24 h after aldosterone injection. Rat RPE-choroid complexes were used for RNA sequencing and analysis. Uninephrectomy/aldosterone/salt (NAS) model was created in wild-type C57BL/6 mice. After 6 weeks, histology of mouse posterior segments were observed ex vivo. Gene expression in the RPE-choroid complex was analyzed using quantitative PCR. Acute intravitreous injection of aldosterone induced posterior segment inflammation observed on OCT. RNA sequencing of rat RPE-choroid complexes revealed up-regulation of pathways involved in inflammation, oxidative stress and RNA procession, and down-regulation of genes involved in synaptic activity, muscle contraction, cytoskeleton, cell junction and transporters. Chronic aldosterone/salt exposure in NAS model induces retinal edema, choroidal vasodilation and RPE cell dysfunction and migration. Quantitative PCR showed deregulation of genes involved in inflammatory response, oxidative stress, particularly the NOX pathway, angiogenesis and cell contractility. Both rodent models share some common phenotypes and molecular regulations in the RPE-choroid complex that could contribute to pachychoroid epitheliopathy in humans. The difference in inflammatory status relies on different intraocular or systemic route of aldosterone administration and on the different doses of aldosterone exposed to the RPE-choroid complex.
临床前和临床证据表明，醛固酮和/或糖皮质激素引起的盐皮质激素受体 (MR) 过度激活对视网膜和视网膜色素上皮 (RPE)-脉络膜复合物有害。然而，驱动这些效应的确切分子机制仍知之甚少，并且醛固酮对视网膜和 RPE/脉络膜的慢性暴露的病理后果尚未完全探索。我们旨在破译大鼠 RPE-脉络膜复合物对眼内醛固酮注射的转录组调控，并探讨系统性慢性醛固酮暴露对小鼠 RPE/脉络膜形态和基因调控的影响。高剂量的醛固酮 (100 nM) 被眼内注射到 Lewis 大鼠的眼睛中，以产生能够在 RPE-脉络膜复合物的顶端侧诱导分子反应的醛固酮剂量。在醛固酮注射前后使用光学相干断层扫描 (OCT) 评估体内后节形态。使用 RNA 测序和分析研究大鼠 RPE-脉络膜复合物。在野生型 C57BL/6 小鼠中创建单侧肾切除术/醛固酮/盐 (NAS) 模型。6 周后，对小鼠后节进行离体组织学观察。使用定量 PCR 分析 RPE-脉络膜复合物中的基因表达。急性眼内注射醛固酮可在 OCT 上观察到后节炎症。大鼠 RPE-脉络膜复合物的 RNA 测序显示，参与炎症、氧化应激和 RNA 加工的途径上调，而参与突触活动、肌肉收缩、细胞骨架、细胞连接和转运体的基因下调。NAS 模型中慢性醛固酮/盐暴露可诱导视网膜水肿、脉络膜扩张和 RPE 细胞功能障碍和迁移。定量 PCR 显示参与炎症反应、氧化应激、特别是 NOX 途径、血管生成和细胞收缩性的基因失调。这两种啮齿动物模型在 RPE-脉络膜复合物中具有一些共同的表型和分子调控，这可能导致人类的肥厚性脉络膜病变。炎症状态的差异取决于醛固酮进入眼内或系统的途径不同，以及暴露于 RPE-脉络膜复合物的醛固酮剂量不同。
