Role of the prorenin receptor in blood pressure and autonomic control through the local activation of the renin angiotensin system in the brainstem

肾素原受体通过脑干肾素血管紧张素系统的局部激活在血压和自主控制中的作用

• 批准号: 10469651
• 负责人: Pablo Nakagawa
• 金额: $ 11.25万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469651
• 关键词: Ablation; Acute; Affect; Anatomy; Angiotensin II; Angiotensinogen; Angiotensins; Area; Attenuated; Binding; Blood Circulation; Blood Pressure; Brain; Brain Stem; Brain region; Calcium; Cardiovascular Abnormalities; Cardiovascular Manifestation; Cardiovascular system; Cause of Death; Cell Nucleus; Cells; Data; Dependovirus; Disinhibition; Endocrine; Enzymes; Event; Excision; Extracellular Space; GTP-Binding Proteins; Gene Deletion; Generations; Genes; Genetic; Goals; Heart Diseases; Hormones; Hypertension; In Vitro; Inactive Renin; Institution; Juxtaglomerular Cell; Kidney; Laboratories; Laboratory Research; Longitudinal Studies; LoxP-flanked allele; Mediating; Metabolic Control; Microinjections; Modeling; Molecular; Molecular Profiling; Mus; Myocardial Infarction; Nerve; Neurons; Organ; Peptides; Physiological; Play; Population; Problem Solving; Protein Isoforms; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Receptor, Angiotensin, Type 1; Recombinants; Renin; Renin-Angiotensin System; Research; Risk Factors; Role; Scientific Advances and Accomplishments; Scientist; Secretory Vesicles; Sensitivity and Specificity; Signal Transduction; Signaling Protein; Stroke; System; Techniques; Testing; Tissues; Training; Transgenic Mice; Translations; United States; autocrine; blood pressure control; blood pressure elevation; driving force; in vivo; insight; neurogenic hypertension; normotensive; novel; paracrine; prevent; prorenin receptor; receptor; receptor binding; release of sequestered calcium ion into cytoplasm; response; sensor; skills; tool; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Hypertension affects nearly half of the population and it is the principal risk factor for heart attack and stroke, the leading first and third cause of death in the United States. The renin-angiotensin system (RAS), is one of the most studied mechanisms of blood pressure control. The classical view of the RAS involves a sequential cleavage of the substrate angiotensinogen resulting in the elevation of circulating angiotensin II (ANG). In addition to functioning within the circulation as a classical (endocrine) hormone system, several tissues including the brain produce local acting ANG, supporting the concept that autocrine/paracrine/intracrine versions of the RAS act locally within these tissues. However, this scientific premise has been challenged due to the difficulties to detect renin in extrarenal organs. Indeed, the enzymes catalyzing the hydrolytic removal of the prosegment, which is required for the activation of renin, are absent in extrarenal tissues. Utilizing cutting edge molecular techniques with superior specificity and sensitivity we were able to identify specific cells located in the rostral ventrolateral medulla (RVLM) that express renin. We also observed that in a model of neurogenic hypertension, such as mice lacking the alternative renin isoform (renin-b), there is a disinhibition of the classical renin isoform (renin-a) encoding preprorenin within the RVLM. This data has been our driving force to interrogate what is the function of renin- expressing cells within the RVLM, and moreover, are these cells initiating ANG signaling within the areas adjacent to the RVLM by secreting prorenin to the extracellular space which is abundant of angiotensinogen? A key step to answer these questions is to decipher how prorenin is activated. The discovery of prorenin receptor (PRR), a receptor that binds prorenin and induces its activation without the cleavage of the prosegment, might be a key player to solve this problem. In the recent years, several ANG-independent and (pro)renin-independent functions of PRR have been demonstrated. Since then, the role of PRR mediating the local activation of the RAS has been questioned. Given the long-held controversy in this field, our fundamental goal is to clarify the physiological and molecular role of PRR within the RVLM and then to dissociate the actions that are dependent of the RAS versus those that are independent of the generation of ANG. Finally, we propose a transcriptomic approach to identify the neuronal and molecular signature of the renin-expressing cells within the RVLM. Collectively, this project will facilitate continued technical, intellectual, and professional training for the candidate, and assist in the establishment of an independent research laboratory at an academic research institution.

项目概要/摘要 高血压影响着近一半的人口，它是心脏病发作和中风的主要危险因素， 美国第一和第三大死因。 肾素-血管紧张素系统（RAS）是研究最多的血压控制机制之一。这 RAS 的经典观点涉及底物血管紧张素原的连续裂解，从而产生 循环血管紧张素 II (ANG) 升高。除了作为经典在流通中发挥作用之外 （内分泌）激素系统，包括大脑在内的多个组织产生局部作用的 ANG，支持 RAS 的自分泌/旁分泌/内分泌版本在这些组织内局部发挥作用的概念。 然而，由于难以检测肾外肾素，这一科学前提受到了挑战。 器官。事实上，酶催化前链段的水解去除，这是 肾素的激活，在肾外组织中不存在。利用尖端分子技术和卓越的 特异性和敏感性我们能够识别位于延髓头端腹外侧 (RVLM) 的特定细胞 表达肾素。我们还观察到，在神经源性高血压模型中，例如缺乏 替代肾素同种型（肾素-b），对经典肾素同种型（肾素-a）编码有去抑制作用 RVLM 内的前肾素原。这些数据一直是我们探究肾素功能的动力。 RVLM 内的表达细胞，此外，这些细胞是否在该区域内启动 ANG 信号传导 通过将肾素原分泌到富含血管紧张素原的细胞外空间，与 RVLM 相邻？一个 回答这些问题的关键一步是破译肾素原是如何被激活的。肾素原受体的发现 (PRR) 是一种结合肾素原并诱导其激活而不裂解前段的受体，可能 成为解决这个问题的关键人物。近年来，一些不依赖ANG和（原）肾素的研究 PRR的功能已得到证实。自此，PRR 介导 RAS 局部激活的作用 已被质疑。鉴于这一领域长期存在的争议，我们的根本目标是澄清 PRR 在 RVLM 中的生理和分子作用，然后分离相关的作用 RAS 与独立于 ANG 产生的那些。最后，我们提出了转录组学 方法来识别 RVLM 内肾素表达细胞的神经元和分子特征。 总的来说，该项目将促进持续的技术、智力和专业培训 候选人，并协助在学术研究中建立独立的研究实验室 机构。