Pro/renin receptor-mediated signaling in pathogenesis of diabetic retinopathy

项目摘要： 大量的实验和临床证据表明， 肾素血管紧张素系统（RAS），导致血管紧张素II（Ang II）浓度升高， 有助于增加炎症、氧化应激和代谢综合征的发展， 肥胖、糖尿病及其并发症，包括DR。除了循环RAS， RAS也在包括眼睛在内的不同组织中表达。局部RAS功能障碍 导致糖尿病的组织病理生理学和终末器官损伤。但具体 眼部RAS对糖尿病视网膜病理生理学的作用机制尚不清楚， 很好理解原肾素，活性肾素的前体，RAS中的限速酶 级联反应是糖尿病患者的血浆和DR患者的眼液高度升高。的 其受体原/肾素受体（PRR）的发现，提供了一个机制的联系，提高 已证实，该途径的激活可增加血管紧张素II（Ang II）水平， 在组织水平上产生，以及直接激活下游信号传导，而不依赖于Ang II作用，两者均导致终末器官损伤。除了作为一个重要的 PRR是RAS的组成部分，PRR是液泡H+-ATP酶（V-ATP酶）的组成部分， 在细胞内区室的酸化和细胞pH稳态中起核心作用。 PRR还充当Wnt信号复合物和V-ATP酶之间的衔接蛋白。此外，委员会认为， 可溶性PRR（sPRR）由蛋白酶介导的切割产生， 包括DR在内的各种病理状态。越来越多的证据表明， 升高的sPRR;然而，sPRR有助于这些疾病发病机制的机制 条件还没有完全了解。我们假设，升高的前肾素、PRR及其 可溶性形式（sPRR）通过多种途径参与DR发病，导致局部RAS 激活，以及独立于Ang II作用的信号传导事件。这项提案的目的是 （1）确定原肾素诱导的，PRR介导的信号通路的机制， DR的发病机制;（2）确定升高的sPRR是否介导了原肾素刺激效应 并激活视网膜中的血管紧张素II依赖性途径;和（3）确定其作用， 原肾素和sPRR对V-ATP酶功能和相关细胞过程的作用机制。 总的来说，拟议的研究将通过以下方式确定机制和信号通路： 其中原肾素、原/肾素受体及其可溶性形式有助于视网膜神经血管 糖尿病的功能障碍。了解这些途径之间的机制和关系 将推动糖尿病视网膜病变更有效疗法的发展。

Project Summary: A large body of experimental and clinical evidence has demonstrated that dysregulation of the renin angiotensin system (RAS), resulting in elevated concentrations of Angiotensin II (Ang II), contributes to increased inflammation, oxidative stress, and development of metabolic syndrome, obesity, diabetes and its complications including DR. In addition to circulating RAS, components of RAS are also expressed in different tissues including the eye. Local RAS dysfunction contributes to tissue pathophysiology and end-organ damage in diabetes. However, the exact mechanisms by which ocular RAS contribute to retinal pathophysiology in diabetes are still not well-understood. Prorenin, a precursor of the active renin, the rate-limiting enzyme in RAS cascade, is highly elevated plasma of diabetic patients and ocular fluid of DR patients. The discovery of its receptor, pro/renin receptor (PRR), provided a mechanistic link of elevated prorenin in pathogenesis of DR. Activation of this pathway has been shown to increase Ang II production at tissue level, as well as direct activation of downstream signaling independent of Ang II action, both of which contribute to end-organ damage. In addition to function as a crucial component of RAS, PRR is an integral component of vacuolar H+-ATPase (V-ATPase), which plays central roles in the acidification of intracellular compartments and cellular pH homeostasis. PRR also acts an adaptor protein between the Wnt signaling complex and V-ATPase. Moreover, a soluble form of PRR (sPRR) is produced by protease-mediated cleavage and is elevated under various pathological conditions including DR. Increasing evidence implicates a pathological role of elevated sPRR; however, the mechanisms by which sPRR contribute to pathogenesis of these conditions are still not fully understood. We hypothesize that elevated prorenin, PRR and its soluble form (sPRR) contribute to pathogenesis of DR by multiple pathways, leading to local RAS activation, as well as signaling events independent of Ang II action. The goal of this proposal is to (1) determine the mechanisms of prorenin-induced, PRR-mediated signaling pathways in pathogenesis of DR; (2) determine whether elevated sPRR mediate prorenin-stimulated effects and activates Ang II-dependent pathways in the retina; and (3) determine the effects and mechanisms of prorenin and sPRR on V-ATPase function and associated cellular processes. Collectively, the proposed studies will determine the mechanism(s) and signaling pathways by which prorenin, pro/renin receptor, and its soluble form contribute to retinal neurovascular dysfunction in diabetes. Knowledge of the mechanisms and relationship between these pathways will drive the development of more effective therapies for diabetic retinopathy.