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.

项目总结： 大量的实验和临床证据表明，细胞的调节失调 肾素血管紧张素系统(RAS)，导致血管紧张素II(Ang II)浓度升高， 会增加炎症、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除循环RAS外，还包括 RAS在包括眼睛在内的不同组织中也有表达。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害。然而，准确的 眼部RAS在糖尿病视网膜病理生理中的作用机制尚不清楚 很好理解。原肾素，活性肾素的前体，RAS的限速酶 CASCADE是糖尿病患者血浆和DR患者眼液的高度升高。这个 其受体原/肾素受体(PRR)的发现提供了一种升高的机制联系。 原肾素在DR发病机制中的作用研究表明，激活该通路可增加Ang II 组织水平的生产，以及不依赖血管紧张素转换酶的下游信号的直接激活 II行动，这两者都会造成终末器官损害。除了起到至关重要的作用 RAS的组成成分PRR是液泡H+-ATPase(V-ATPase)的组成部分，它 在细胞内隔室的酸化和细胞pH动态平衡中起核心作用。 PrR还在Wnt信号复合体和V-ATPase之间起到适配蛋白的作用。此外， 一种可溶性形式的PRR(SPRR)是由蛋白酶介导的切割产生的，在 包括Dr.在内的各种病理情况越来越多的证据表明 SPRR升高；然而，sPRR在这些疾病的发病机制中起作用 目前还没有完全了解这些情况。我们假设PRORENIN、PRR和其 可溶性形式(SPRR)通过多种途径参与DR的发病，导致局部RAS 激活，以及独立于Ang II作用的信号事件。这项提议的目标是 为了(1)确定Prorenin诱导的、PrR介导的信号转导通路的机制 糖尿病视网膜病变的发病机制；(2)确定sPRR升高是否介导肾素原刺激效应 并激活视网膜中依赖血管紧张素II的通路；以及(3)确定其作用和 Prorenin和sPRR对V-ATPase功能及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(S)和信号通路 哪种前肾素、前/肾素受体及其可溶性形式与视网膜神经血管有关 糖尿病中的功能障碍。对这些途径的机制和相互关系的认识 将推动开发更有效的糖尿病视网膜病变治疗方法。