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

糖尿病视网膜病变发病机制中Pro/肾素受体介导的信号传导

• 批准号: 10718033
• 负责人: Qiuhong Li
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718033
• 关键词: Adaptor Signaling Protein; Angiotensin II; Animal Model; Animals; Binding; Blindness; Blood Circulation; Cardiovascular Diseases; Catalytic Domain; Cell physiology; Cells; Clinical; Complex; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Diabetic Retinopathy; Enzymes; Event; Eye; Functional disorder; Generations; Goals; Human; Inactive Renin; Inflammation; Inflammatory; Kidney; Knowledge; Link; Liquid substance; MAP Kinase Gene; MAPK3 gene; Mediating; Metabolic syndrome; Mitogens; Molecular Conformation; Obesity; Organ; Oxidative Stress; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Plasma; Play; Prevention strategy; Production; Protein Kinase; Publishing; Reactive Oxygen Species; Renin; Renin-Angiotensin System; Reporting; Retina; Rodent; Role; Signal Pathway; Signal Transduction; Testing; Tissues; WNT Signaling Pathway; aging population; antagonist; diabetic; diabetic patient; effective therapy; in vitro Assay; inhibitor; neurovascular; pH Homeostasis; proliferative diabetic retinopathy; prorenin receptor; receptor; receptor binding; receptor function; receptor-mediated signaling; response; therapeutically effective; type I and type II diabetes; vacuolar H+-ATPase

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.

项目概要： 大量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， 导致炎症增加、氧化应激和代谢综合征的发生， 肥胖、糖尿病及其并发症，包括 DR。除了循环 RAS 之外，组件 RAS 也在包​​括眼睛在内的不同组织中表达。局部RAS功能障碍 有助于糖尿病的组织病理生理学和终末器官损伤。然而，确切的 眼部 RAS 促进糖尿病视网膜病理生理学的机制仍不清楚 很好理解。肾素原，活性肾素的前体，RAS 中的限速酶 级联，是糖尿病患者的血浆和DR患者的眼液高度升高。这 其受体原/肾素受体 (PRR) 的发现提供了升高的机制联系 肾素原在 DR 发病机制中的作用。该通路的激活已被证明可以增加 Ang II 组织水平的产生，以及独立于 Ang 的下游信号传导的直接激活 II 作用，两者都会导致终末器官损伤。除了起到关键作用外 PRR 是 RAS 的组成部分，是液泡 H+-ATP 酶 (V-ATP 酶) 的组成部分， 在细胞内区室酸化和细胞 pH 稳态中发挥核心作用。 PRR 还充当 Wnt 信号复合物和 V-ATP 酶之间的衔接蛋白。而且， PRR (sPRR) 的可溶形式是由蛋白酶介导的切割产生的，并在以下条件下升高： 各种病理状况，包括 DR。越来越多的证据表明存在病理作用 sPRR 升高；然而，sPRR 促进这些疾病发病机制的机制 条件尚未完全了解。我们假设升高的肾素原、PRR 及其 可溶性形式 (sPRR) 通过多种途径促进 DR 的发病机制，导致局部 RAS 激活，以及独立于 Ang II 作用的信号事件。该提案的目标是 (1) 确定肾素原诱导的、PRR 介导的信号通路的机制 DR 的发病机制； (2) 确定sPRR升高是否介导肾素原刺激作用 并激活视网膜中的 Ang II 依赖性通路； (3) 确定效果和 肾素原和 sPRR 对 V-ATP 酶功能和相关细胞过程的机制。 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： 肾素原、肾素原/肾素受体及其可溶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 将推动开发更有效的糖尿病视网膜病变疗法。