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: 10669056
• 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/10669056
• 关键词: Ablation; Acute; Affect; Anatomy; Angiotensin II; Angiotensin II Receptor; Angiotensinogen; Angiotensins; Area; Attenuated; Binding; Blood Pressure; Brain; Brain Stem; Brain region; Calcium; Cardiovascular Abnormalities; Cardiovascular Manifestation; Cardiovascular system; Cause of Death; Cell Nucleus; Cells; Circulation; Data; Dependovirus; Disinhibition; Dissociation; 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; Protein Isoforms; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Receptor, Angiotensin, Type 1; Recombinants; Renal Tissue; 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; genetic approach; in vivo; insight; neurogenic hypertension; normotensive; novel; paracrine; prevent; prorenin receptor; receptor; receptor binding; release of sequestered calcium ion into cytoplasm; response; sensor; single nucleus RNA-sequencing; skills; tool; 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.

项目总结/文摘

项目成果

Patch-to-Seq and Transcriptomic Analyses Yield Molecular Markers of Functionally Distinct Brainstem Serotonin Neurons.

• DOI: 10.3389/fnsyn.2022.910820
• 发表时间: 2022
• 期刊: FRONTIERS IN SYNAPTIC NEUROSCIENCE
• 影响因子: 3.7
• 作者: Mouradian, Gary C., Jr.;Liu, Pengyuan;Nakagawa, Pablo;Duffy, Erin;Gomez Vargas, Javier;Balapattabi, Kirthikaa;Grobe, Justin L.;Sigmund, Curt D.;Hodges, Matthew R.
• 通讯作者: Hodges, Matthew R.

Methods for the Comprehensive in vivo Analysis of Energy Flux, Fluid Homeostasis, Blood Pressure, and Ventilatory Function in Rodents.

• DOI: 10.3389/fphys.2022.855054
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Reho JJ;Nakagawa P;Mouradian GC Jr;Grobe CC;Saravia FL;Burnett CML;Kwitek AE;Kirby JR;Segar JL;Hodges MR;Sigmund CD;Grobe JL
• 通讯作者: Grobe JL

Genetic Ablation of Prorenin Receptor in the Rostral Ventrolateral Medulla Influences Blood Pressure and Hydromineral Balance in Deoxycorticosterone-Salt Hypertension.

• DOI: 10.1093/function/zqad043
• 发表时间: 2023
• 期刊: FUNCTION
• 影响因子: 6.2
• 作者: Mathieu, Natalia M.;Fekete, Eva M.;Muskus, Patricia C.;Brozoski, Daniel T.;Lu, Ko-Ting;Wackman, Kelsey K.;Gomez, Javier;Fang, Shi;Reho, John J.;Grobe, Connie C.;Vazirabad, Ibrahim;Mouradian Jr, Gary C.;Hodges, Matthew R.;Segar, Jeffrey L.;Grobe, Justin L.;Sigmund, Curt D.;Nakagawa, Pablo
• 通讯作者: Nakagawa, Pablo

Melanocortin MC4R receptor is required for energy expenditure but not blood pressure effects of angiotensin II within the mouse brain.

黑皮质素 MC4R 受体是小鼠大脑内能量消耗所必需的，但血管紧张素 II 的血压作用并非如此。

• DOI: 10.1152/physiolgenomics.00015.2022
• 发表时间: 2022
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: Oliveira,Vanessa;Riedl,RuthA;Claflin,KristinE;Mathieu,NataliaM;Ritter,McKenzieL;Balapattabi,Kirthikaa;Wackman,KelseyK;Reho,JohnJ;Brozoski,DanielT;Morgan,DonaldA;Cui,Huxing;Rahmouni,Kamal;Burnett,ColinML;Nakagawa,Pablo

Role of the Peroxisome Proliferator Activated Receptors in Hypertension.

过氧化物酶体增殖物在高血压中活化受体的作用。

• DOI: 10.1161/circresaha.120.318062
• 发表时间: 2021-04-02
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Fang S;Livergood MC;Nakagawa P;Wu J;Sigmund CD
• 通讯作者: Sigmund CD