Expression and Regulation of Retinal Angiotensin II

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。 在高血压和非胰岛素依赖型糖尿病（2型）中发生的血管紧张素（Ang）II和胰岛素水平的增加可能有助于小眼动脉内的这一过程。 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）在糖尿病视网膜病变的治疗中赋予治疗益处。 虽然糖尿病视网膜并发症的发病机制尚未完全了解，新出现的证据涉及RAS，其促有丝分裂和营养作用及其对血管生成的影响。 血管紧张素II可以在视网膜局部产生，并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，视网膜是血管紧张素II在高血压和/或糖尿病大鼠的靶组织。我们将在易卒中的自发性高血压大鼠（SHRSP）与链脲佐菌素诱导的糖尿病，现在显示出发展的迹象，糖尿病视网膜病变，逆转血管紧张素受体拮抗剂这一假设进行测试。 具体目标是：1）检测血管紧张素受体亚型转录本和蛋白的组织特异性表达。2）检测血管紧张素原、肾素、血管紧张素转换酶和血管紧张素Ⅱ在视网膜中的组织特异性表达。 分子、生物化学和免疫组织化学方法将结合起来。3)目的：探讨RAS生理和遗传紊乱时视网膜血管紧张素Ⅱ的调节机制。 视网膜电图将用于评价视网膜功能，并与尾袖测量的血压相关联。 这些研究不仅将扩大我们对RAS在新组织中的功能的理解，而且可能具有重要的治疗意义。 最终，视网膜血管紧张素受体可以特异性靶向选择性治疗药物，以防止增殖性糖尿病视网膜病变的发展。

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.