Expression and Regulation of Retinal Angiotensin II

视网膜血管紧张素II的表达和调控

• 批准号: 6607887
• 负责人: PREENIE E SENANAYAKE
• 金额: $ 14.8万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607887
• 关键词: RNase protection assay; angiotensin II; angiotensin receptor; autoradiography; diabetic retinopathy; electroretinography; enzyme activity; enzyme linked immunosorbent assay; high performance liquid chromatography; hypertension; immunocytochemistry; in situ hybridization; pathologic process; peptidyl dipeptidase A; polymerase chain reaction; radioimmunoassay; receptor expression; renin angiotensin system; spontaneous hypertensive rat

DESCRIPTION (provided by applicant): The long-term goal of my research is to understand the role of hypertension in the pathogenesis of diabetic retinopathy. In humans and other species with vascularized retinas, the rates of glucose and oxygen utilization by the retina are 3-fold higher than in any other tissue. The retinal circulation is highly sensitive to local tissue metabolic needs and susceptible to damage from circulatory dysfunction. In diabetic patients, capillary non-perfusion has been shown to precede neovascularization. Capillary ischemia could be due at least in part to obstruction caused by abnormal or accelerated growth of vascular smooth muscle cells. The increases in angiotensin (Ang) II and insulin levels that occur in hypertension and non-insulin dependent diabetes (type 2) may contribute to this process within the small ophthalmic arteries. Thus, insulin and Ang II could act in a synergistic manner. Inhibiting the renin-angiotensin system (RAS) confers a therapeutic benefit in the treatment of diabetic retinopathy. Although the pathogenesis of diabetic retinal complications is not fully understood, emerging evidence implicates the RAS, with its mitogenic and trophic actions and its influence on angiogenesis. Ang II may be produced locally in the retina, and could play a role in the development and/or maintenance of proliferative diabetic retinopathy. Our hypothesis is that the retina is a target tissue for Ang II in rats with hypertension and/or diabetes. We will test this hypothesis in the stroke-prone spontaneously hypertensive rat (SHRSP) with streptozocin-induced diabetes, now shown to develop signs of diabetic retinopathy that are reversed by an Ang receptor antagonist. Specific aims are: 1) To determine the tissue-specific expression of Ang receptor subtype transcripts and proteins, 2) To examine tissue-specific expression of angiotensinogen, renin, angiotensin converting enzyme and Ang II in the retina. Molecular, biochemical and immunohistochemical approaches will be combined. 3) To assess the mechanism of regulation of Ang II in the retina under physiological and genetic perturbations of the RAS. Electroretinography will be used to evaluate retinal function, which will be correlated with blood pressure measured by tail cuff. These studies will not only expand our understanding of the function of the RAS in a novel tissue, but may also have important therapeutic implications. Ultimately retinal Ang receptors could be specifically targeted with selective therapeutic agents to prevent the development of proliferative diabetic retinopathy.

描述（由申请人提供）：我研究的长期目标是了解高血压在糖尿病视网膜病变发病机制中的作用。 在人类和其他具有血管化视网膜的物种中，视网膜对葡萄糖和氧气的利用率比任何其他组织高 3 倍。 视网膜循环对局部组织代谢需求高度敏感，并且容易受到循环功能障碍的损害。在糖尿病患者中，毛细血管无灌注已被证明先于新血管形成。 毛细血管缺血可能至少部分是由于血管平滑肌细胞异常或加速生长引起的阻塞所致。 高血压和非胰岛素依赖型糖尿病（2 型）中血管紧张素 (Ang) II 和胰岛素水平的升高可能有助于眼小动脉内的这一过程。 因此，胰岛素和Ang II可以协同作用。 抑制肾素-血管紧张素系统（RAS）可在糖尿病视网膜病变的治疗中发挥治疗作用。 尽管糖尿病视网膜并发症的发病机制尚不完全清楚，但新出现的证据表明 RAS 具有促有丝分裂和营养作用及其对血管生成的影响。 Ang II 可能在视网膜局部产生，并且可能在增殖性糖尿病视网膜病变的发展和/或维持中发挥作用。 我们的假设是，视网膜是患有高血压和/或糖尿病的大鼠中 Ang II 的靶组织。我们将在患有链脲佐菌素诱导糖尿病的易发生中风的自发性高血压大鼠（SHRSP）中测试这一假设，该大鼠现已显示出出现糖尿病性视网膜病变的迹象，而血管紧张素受体拮抗剂可以逆转这些迹象。 具体目标是：1）确定血管紧张素受体亚型转录物和蛋白质的组织特异性表达，2）检查视网膜中血管紧张素原、肾素、血管紧张素转换酶和血管紧张素II的组织特异性表达。 分子、生物化学和免疫组织化学方法将被结合起来。 3) 评估RAS生理和遗传扰动下视网膜Ang II的调节机制。 视网膜电图检查将用于评估视网膜功能，这将与尾套测量的血压相关。 这些研究不仅将扩大我们对新组织中 RAS 功能的理解，而且可能具有重要的治疗意义。 最终，选择性治疗药物可以专门针对视网膜血管紧张素受体，以预防增殖性糖尿病视网膜病变的发展。