Renal AT2 Receptors in Hypertension

高血压中的肾 AT2 受体

基本信息

批准号：
10542716
负责人：
SUSANNA R KELLER
金额：
$ 68.2万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542716
关键词：
AGTR2 gene Acute Address Adult Affect Age Agonist Angiotensin II Angiotensin III Angiotensins Apical Blood Pressure Blood Vessels Cell membrane Cells Cessation of life Chronic Cyclic AMP Cyclic AMP Receptor Protein Cyclic AMP-Dependent Protein Kinases Cyclic GMP Defect Development Disease Dopamine Essential Hypertension Excretory function Fenoldopam Functional disorder Funding Goals Heart Human Hypertension Impairment Inbred SHR Rats Infusion procedures Intracellular translocation Kidney Knockout Mice Mediating Microtubules Molecular Mus Natriuresis Pathogenesis Pathway interactions Peptides Pharmacotherapy Population Production Protein phosphatase Proximal Kidney Tubules Rattus Receptor Activation Receptor Inhibition Receptor Signaling Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin System Risk Factors Role Signal Pathway Signal Transduction Site Sodium Sodium Chloride Techniques Testing Type 2 Angiotensin II Receptor United States Water absorption antagonist blood pressure control blood pressure reduction disability hypertension prevention hypertensive in vivo molecular targeted therapies normotensive novel drug class premature prevent receptor recruit response restoration saluretic therapeutic target

AGTR2 gene Acute Address Adult Affect Age Agonist Angiotensin II Angiotensin III Angiotensins Apical Blood Pressure Blood Vessels Cell membrane Cells Cessation of life Chronic Cyclic AMP Cyclic AMP Receptor Protein Cyclic AMP-Dependent Protein Kinases Cyclic GMP Defect Development Disease Dopamine Essential Hypertension Excretory function Fenoldopam Functional disorder Funding Goals Heart Human Hypertension Impairment Inbred SHR Rats Infusion procedures Intracellular translocation Kidney Knockout Mice Mediating Microtubules Molecular Mus Natriuresis Pathogenesis Pathway interactions Peptides Pharmacotherapy Population Production Protein phosphatase Proximal Kidney Tubules Rattus Receptor Activation Receptor Inhibition Receptor Signaling Receptor, Angiotensin, Type 1 Regulation Renin-Angiotensin System Risk Factors Role Signal Pathway Signal Transduction Site Sodium Sodium Chloride Techniques Testing Type 2 Angiotensin II Receptor United States Water absorption antagonist blood pressure control blood pressure reduction disability hypertension prevention hypertensive in vivo molecular targeted therapies normotensive novel drug class premature prevent receptor recruit response restoration saluretic therapeutic target

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项目摘要

PROJECT SUMMARY/ABSTRACT Hypertension (HT) affects ~48% of the US population. Increased renal sodium (Na+) retention is a major contributor to the development of HT. The renal angiotensin type-1 receptor (AT1R), activated predominantly by angiotensin (Ang) II, is both necessary and sufficient for inducing and sustaining HT during Ang II infusion. Increased Na+ reabsorption in renal proximal tubule cells (RPTC) is a major determinant of this response. The role of the angiotensin type-2 receptor (AT2R) in Na+ excretion and blood pressure (BP) control is less well understood. AT2Rs are expressed in adult kidneys primarily in RPTC. Our past studies provided evidence for a major role of RPT AT2Rs in the inhibition of renal Na+ reabsorption. Recently, we identified a defect in AT2R- mediated natriuresis in spontaneously hypertensive rats (SHR) that pre-dates HT and can be circumvented by direct renal administration of cyclic GMP (cGMP). Our results suggest that defective AT2R-induced natriuresis may contribute to the pathogenesis of HT in SHR. The goals of this project are to (1) conclusively demonstrate the role of AT2Rs in BP control using our newly developed RPTC-AT2R deficient mice, (2) identify downstream AT2R signaling pathways mediating natriuresis, (3) characterize the primary RPTC AT2R defect(s) in SHR at the cellular and molecular levels, and (4) validate renal cGMP and protein phosphatase 2A (PP2A) activation as specific therapeutic targets for HT. These goals will be addressed under three specific aims: (1) To test the hypothesis that RPT AT2Rs are required for the regulation of Na+ excretion and blood pressure; (2) To test the hypothesis that protein phosphatase 2A (PP2A) initiates and sustains RPTC AT2R signaling to induce natriuresis; and (3) To test the hypothesis that intrarenal PP2A activation and/or restoration of cGMP levels/signaling can normalize blood pressure in hypertensive SHR and RPTC-selective AT2R knockout mice. The project will apply a combination of state-of-the-art in vivo and cellular and molecular techniques to determine mechanisms by which AT2R regulates Na+ excretion and BP. These studies will help define the pathophysiology of HT and open the door to new classes of drugs for the treatment of human primary HT.

项目摘要/摘要高血压（HT）影响约48％的美国人口。肾脏钠（Na+）保留率增加是主要的 HT发展的贡献者。肾血管紧张素1型受体（AT1R）主要激活通过血管紧张素（ANG）II，对于在ANG II输注期间诱导和维持HT既需要且足够。肾近端小管细胞（RPTC）中Na+的重吸收增加是该反应的主要决定因素。这血管紧张素2受体（AT2R）在Na+排泄和血压（BP）对照中的作用不太好理解。 AT2RS在RPTC中主要在成年肾脏中表达。我们过去的研究提供了证据 RPT AT2RS在肾脏Na+重吸收的抑制中的主要作用。最近，我们确定了AT2R-的缺陷自发性高血压大鼠（SHR）中介导的纳特里雷SIS，可以预先避免肾脏GMP（CGMP）的直接肾脏给药。我们的结果表明，AT2R诱导的Natriuresis有缺陷可能有助于SHR中HT的发病机理。该项目的目标是（1）最终证明使用我们新开发的RPTC-AT2R缺陷小鼠AT2RS在BP控制中的作用，（2）识别下游 AT2R信号传导途径介导Natriuresis，（3）表征SHR中的主要RPTC AT2R缺陷（S）细胞和分子水平，以及（4）验证肾脏CGMP和蛋白质磷酸酶2A（PP2A）激活作为HT的特定治疗靶标。这些目标将在三个具体目标下解决：（1）测试假设RPT AT2RS需要调节Na+排泄和血压。（2）测试假设蛋白质磷酸酶2a（PP2A）启动并维持RPTC AT2R信号传导纳特里雷斯；（3）检验了肾内PP2A激活和/或恢复CGMP的假设水平/信号传导可以使高血压SHR和RPTC选择性AT2R敲除小鼠的血压归一化。该项目将在体内和细胞和分子技术的结合中结合使用确定AT2R调节Na+排泄和BP的机制。这些研究将有助于定义 HT的病理生理学，并为治疗人类原发性HT的新药物打开了大门。