Renal Pericytes as a Target for Angiotensin II Signaling in Hypertension

肾周细胞作为高血压血管紧张素 II 信号传导的靶标

基本信息

批准号：
10654833
负责人：
Jonathan W Nelson
金额：
$ 12.75万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654833
关键词：
Angiotensin II Angiotensin II Receptor Angiotensin Receptor Angiotensins Animals Attenuated Automobile Driving Bioinformatics Biology Biomedical Research Blood Pressure Blood Vessels Blood capillaries Blood flow Cells Chronic Kidney Failure Coal Coupled Data Set Development Diameter Drug Targeting Fluorescence-Activated Cell Sorting Functional disorder GTP-Binding Proteins Gene Targeting Genetic Genetic Transcription Glomerular Filtration Rate Health Heart failure Human Hypertension Image Infusion procedures Injury to Kidney Kidney Kidney Diseases Knockout Mice Knowledge Link Measures Mediating Mentors Mentorship Microsurgery Molecular Molecular Biology Mus Myofibroblast Natriuresis Nephrology Optics Oregon Pathogenicity Pathologic Pathology Pathway interactions Peptides Pericytes Physiology Play Population Population Distributions Principal Investigator Process Publications Publishing Receptor, Angiotensin, Type 1 Renal Blood Flow Renal Hypertension Renal function Renin-Angiotensin System Research Research Personnel Research Proposals Resistance Role Science Signal Transduction Slice Sorting Systemic blood pressure Techniques Testing Tissues Training Universities Vascular Diseases Vascular Morphologic Change blood pressure control blood pressure elevation blood pressure regulation career career development cell type comparison control decubitus ulcer defined contribution design experimental study hypertension treatment in vivo kidney vascular structure knockout animal next generation novel novel therapeutics pharmacologic programs receptor renin hypertension single cell analysis single-cell RNA sequencing skills tool transcriptional reprogramming vasoconstriction

项目摘要

PROJECT SUMMARY The renin-angiotensin-system (RAS) plays a central role in regulating systemic blood pressure. This is illustrated by the proven benefit of RAS-targeted drugs such as angiotensin receptor blockers, which are critical to the treatment of hypertension, heart failure and kidney disease. The actions of the RAS depend on the peptide angiotensin II (ang II) acting on cells that express the G-protein coupled type 1 angiotensin receptor (human: AT1; mouse: AT1a). Our group has been at the forefront of unmasking cell-specific roles of ang II signaling within different cell populations in the kidney. These studies have revealed novel roles for ang II to act distinctly in different cell types to drive pathogenic mechanisms associated with hypertension. This suggests that the overall, systemic effect of ang II on blood pressure results from the cumulative actions of ang II on multiple cell types within the body. Our preliminary studies analyzed recently published single-cell RNA Sequencing datasets to explore the cell-specific expression of angiotensin receptors within the kidney. We find that pericytes, a mural cell type associated with capillaries and the glomerulus, express the mouse AT1a receptor. Additionally, we confirmed this by measuring AT1a expression from rapidly sorted pericytes from the kidney. However, the role of angiotensin signaling in pericytes remains under-examined. This is despite multiple lines of evidence that suggest renal pericytes play a central role in regulating blood pressure and renal injury, angiotensin-linked processes which are pathologically altered in hypertension and chronic kidney disease. This project will test the overall hypothesis that angiotensin II signaling within pericytes contributes to the development of hypertension and renal injury. This candidate has developed a novel mouse line which has inducible pericyte-specific deletion of the AT1a receptor. First, the contribution of pericyte ang II signaling to blood pressure control will be determined under baseline conditions and during ang II hypertension. Next, the effect of ang II signaling within pericytes on renal injury in the context of hypertension will be assessed. This research will be carried out by an applicant with excellent training in biomedical research with a strong publication record. The training for this proposal will occur at Oregon Health & Science University within the Division of Nephrology and Hypertension under the primary mentorship of Dr. Susan Gurley a leader in the field of cell-specific actions of RAS signaling in the kidney. This project will also be supported by two other co-mentors: Dr. Anusha Mishra, an expert on pericyte biology and microvascular blood flow, and Dr. Lynne Sakai, an expert on vascular fibrotic signaling. Career development activities include training in mouse micro-surgery, ex vivo slice imaging, assessment of renal pathology, and bioinformatic analysis of single-cell RNA sequencing datasets. This training is designed to launch the candidate to lead the next generation of kidney research with well-honed skills in animal physiology and molecular biology. This will setup the candidate to meet his long-term career coal of becoming an independent investigator focusing on the cellular and molecular causes of hypertension and renal injury.

项目摘要肾素 - 血管紧张素系统（RAS）在调节系统性血压方面起着核心作用。这说明了通过以RAS为靶向药物（例如血管紧张素受体阻滞剂）的可靠益处，这对治疗高血压，心力衰竭和肾脏疾病。 RA的作用取决于肽血管紧张素II（ANG II）作用于表达G蛋白偶联1型血管紧张素受体的细胞（人： AT1;鼠标：AT1A）。我们的小组一直处于揭露Ang II信号的细胞特异性作用的最前沿在肾脏的不同细胞种群中。这些研究揭示了Ang II明显作用的新作用在不同的细胞类型中，以驱动与高血压相关的致病机制。这表明总体而言，ANG II对血压的全身影响是由ANG II对多个细胞的累积作用产生的体内的类型。我们的初步研究分析了最近发布的单细胞RNA测序数据集探索肾脏中血管紧张素受体的细胞特异性表达。我们发现壁画，壁画与毛细血管和肾小球相关的细胞类型表达小鼠AT1A受体。另外，我们通过测量肾脏快速分类周细胞的AT1A表达来证实这一点。但是，角色周细胞中的血管紧张素信号传导仍然不足。尽管有多种证据建议肾周细胞在调节血压和肾脏损伤，血管紧张素连接方面起着核心作用高血压和慢性肾脏疾病的病理改变的过程。该项目将测试总体假设，即周细胞内血管紧张素II信号传导有助于高血压的发展和肾脏受伤。该候选人开发了一条新型的鼠标线，该系列具有可诱导的周细胞特异性缺失 AT1A受体。首先，周细胞ANG II信号对血压控制的贡献将是在基线条件下和ANG II高血压期间确定。接下来，Ang II信号的效果在高血压的情况下，将评估有关肾脏损伤的周细胞。这项研究将由申请人在生物医学研究方面拥有出色的培训，并具有较强的出版记录。培训提案将在肾脏科和高血压部门的俄勒冈健康与科学大学举行在苏珊·古利（Susan Gurley）博士的主要指导下在肾脏。该项目还将得到另外两位副官员的支持：Anusha Mishra博士，专家周细胞生物学和微血管血流，以及血管纤维化信号的专家Lynne Sakai博士。职业发展活动包括鼠标微手术培训，离体切片成像，评估肾脏病理学和单细胞RNA测序数据集的生物信息学分析。该培训旨在启动候选人，领导下一代具有良好动物生理技能的肾脏研究和分子生物学。这将设立候选人，以满足他的长期职业煤炭独立研究者，重点是高血压和肾脏损伤的细胞和分子原因。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Soluble ACE2 Is Filtered into the Urine.

可溶性 ACE2 被过滤到尿液中。

DOI：
10.34067/kid.0001622022
发表时间：
2022
期刊：
Kidney360
影响因子：
0
作者：
Nelson,JonathanW;Ortiz-Melo,DavidI;Mattocks,NatalieK;Emathinger,JacquelineM;Prescott,Jessica;Xu,Katherine;Griffiths,RobertC;Wakasaki,Rumie;Piehowski,PaulD;Hutchens,MichaelP;Coffman,ThomasM;Gurley,SusanB
通讯作者：
Gurley,SusanB

Machine Learning Illuminates the Extraglomerular Microvasculature.