(Pro)renin receptor mediates obesity induced hypertension
肾素原受体介导肥胖诱发的高血压
基本信息
- 批准号:9391816
- 负责人:
- 金额:$ 36.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-17 至 2021-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAmericanAngiotensinsCardiovascular systemComplicationDataDevelopmentDimerizationDuctal Epithelial CellFRAP1 geneFeedbackFetal DevelopmentFluorescence Resonance Energy TransferFunctional disorderGoalsHypertensionIn VitroInflammationInterleukin-1Interleukin-6KidneyKnock-outKnockout MiceKnowledgeLasersLeadMAPK14 geneMediatingMedicalMicrodialysisMicroscopyMitogen-Activated Protein KinasesModelingMolecularMusNephronsObese MiceObesityPathway interactionsPlayProcessProductionProto-Oncogene Proteins c-aktReceptor, Angiotensin, Type 1RegulationRenal TissueReninResearchResearch ProposalsRoleScanningSignal PathwaySignal TransductionSmooth Muscle MyocytesSodiumTNF geneTechniquesTestingTissuesbasecell typecytokinedimerepithelial Na+ channelin vivomouse modelnovelnovel strategiesnovel therapeutic interventionnovel therapeuticsoverexpressionprogramsreceptorreceptor expressionreceptor functionsmall hairpin RNAtoolvirtual
项目摘要
Hypertension is a common and morbid complication of obesity. The pathophysiologic mechanisms involved in
obesity-induced hypertension are not well elucidated. In this application we propose that (Pro)renin receptor
(PRR), a newly discovered receptor, plays a major role in the development of obesity associated hypertension.
Recent studies confirmed presence of this receptor in adipose tissue and kidneys. The lack of PRR specific
antagonists and the lethality of its total deletion, made it difficult to study this receptor. Currently, the
contribution of PRR to development of obesity-induced hypertension is unknown. In order to study PRR in
adipose tissue and the kidney, this proposal will utilize two novel mouse models namely the inducible
adipocyte specific PRR knockout mouse and the inducible nephron specific PRR knockout mouse. Our
preliminary data demonstrated that obese mice developed hypertension with increased PRR expression and
production of proinflammatory cytokines in adipose tissue and kidneys. These data also suggested that PRR
regulates ENaC expression in the kidney. Based on these data, we propose that PRR contributes to
development of obesity-induced hypertension by enhancing sodium retention. The long-term goal of our
research program is to elucidate the novel mechanisms contributing to the regulation of PRR expression and
function and evaluate its interaction with proinflammatory cytokines, angiotensin subtype AT1 receptor (AT1R),
and ENaC in development of obesity-induced inflammation and hypertension. To achieve this goal, we will
utilize a rationale and novel integrated approaches, including in vitro state-of-the-art cellular and molecular
techniques, in vivo studies utilizing two novel inducible tissue specific PRR knockout mouse models, Laser
Scanning Confocal FRET microscopy and in vivo microdialysis, to rigorously test the proposed hypothesis.
Based on our preliminary data, the central hypothesis of this proposal is that PRR contributes to the
development of obesity-induced hypertension via enhancing adipose tissue and kidney inflammation
and PRR-AT1R dimer formation, leading to increased renal ENaC activity and sodium retention. We
will pursue the following integrated specific aims:
Specific Aim I: To test the hypothesis that adipocyte PRR contributes to the development of obesity-induced
hypertension via enhancing adipocyte IL-1, IL-6, TNFα-renal ENaC pathway.
Specific Aim II: To test the hypothesis that the nephron PRR contributes to the development of obesity-
induced hypertension via enhancing PI3K-AKT-mTOR-SGK1-Nedd4-2-α-ENaC pathway.
Specific Aim III: To test the hypothesis that PRR forms a heterodimer with angiotensin AT1R to enhance
development of obesity-induced hypertension, via ERK-NFB-proinflammatory cytokines-αENaC pathway.
These studies will identify novel pathophysiologic mechanisms related to obesity-induced hypertension and
could lead to the development of new therapeutic strategies in treating this common problem.
高血压是肥胖症的常见并发症。参与的病理生理机制
肥胖引起的高血压还没有很好地阐明。在本申请中,我们提出(Pro)肾素受体
(PRR)是一种新发现的受体,在肥胖相关高血压的发生发展中起重要作用。
最近的研究证实,这种受体存在于脂肪组织和肾脏。缺乏PRR特异性
拮抗剂和其完全缺失的致死性使得研究这种受体变得困难。目前
PRR对肥胖性高血压发生的作用尚不清楚。为了研究PRR,
脂肪组织和肾脏,该提议将利用两种新的小鼠模型,即诱导型
脂肪细胞特异性PRR敲除小鼠和诱导型肾单位特异性PRR敲除小鼠。我们
初步数据表明,肥胖小鼠发生高血压,PRR表达增加,
在脂肪组织和肾脏中产生促炎细胞因子。这些数据还表明,PRR
调节肾脏中的RESENaC表达。基于这些数据,我们提出PRR有助于
通过增加钠潴留发展肥胖性高血压。我们的长期目标是
研究计划是阐明促进PRR表达调节的新机制,
功能,并评估其与促炎细胞因子,血管紧张素亚型AT 1受体(AT 1 R),
和EQUENaC在肥胖引起的炎症和高血压的发展中的作用。为了实现这一目标,我们将
利用基本原理和新的综合方法,包括体外最先进的细胞和分子
技术,利用两种新的可诱导组织特异性PRR敲除小鼠模型的体内研究,激光
扫描共聚焦FRET显微镜和体内微透析,严格测试所提出的假设。
根据我们的初步数据,这一建议的中心假设是,PRR有助于
通过增强脂肪组织和肾脏炎症发展肥胖性高血压
和PRR-AT 1 R二聚体形成,导致肾REPENaC活性和钠潴留增加。我们
将努力实现以下综合具体目标:
具体目的I:检验脂肪细胞PRR有助于肥胖诱导的
高血压通过增强脂肪细胞IL-1、IL-6、TNFα-肾介导的ENaC途径。
具体目的II:检验肾单位PRR促进肥胖发展的假设-
通过增强PI 3 K-AKT-mTOR-SGK 1-Nedd 4 -2-α-ENaC通路诱导高血压。
具体目的III:检验PRR与血管紧张素AT 1 R形成异源二聚体以增强血管紧张素受体表达的假设。
通过ERK-NF κ B-促炎细胞因子-αENaC通路,肥胖诱导的高血压的发展。
这些研究将确定与肥胖引起的高血压相关的新的病理生理机制,
可能会导致新的治疗策略的发展,以治疗这一常见问题。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Helmy M Siragy其他文献
Helmy M Siragy的其他文献
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{{ truncateString('Helmy M Siragy', 18)}}的其他基金
Prorenin Receptor Mediates Early Changes in Diabetic Kidney
肾素原受体介导糖尿病肾脏的早期变化
- 批准号:
8707539 - 财政年份:2008
- 资助金额:
$ 36.23万 - 项目类别:
Prorenin Receptors Mediate Hypertension and Kidney Disease in Diabetes
肾素原受体介导糖尿病中的高血压和肾脏疾病
- 批准号:
7555621 - 财政年份:2008
- 资助金额:
$ 36.23万 - 项目类别:
Prorenin Receptor Mediates Early Changes in Diabetic Kidney
肾素原受体介导糖尿病肾脏的早期变化
- 批准号:
8866434 - 财政年份:2008
- 资助金额:
$ 36.23万 - 项目类别:
Prorenin Receptors Mediate Hypertension and Kidney Disease in Diabetes
肾素原受体介导糖尿病中的高血压和肾脏疾病
- 批准号:
8010846 - 财政年份:2008
- 资助金额:
$ 36.23万 - 项目类别:
Prorenin Receptor Mediates Early Changes in Diabetic Kidney
肾素原受体介导糖尿病肾脏的早期变化
- 批准号:
9086431 - 财政年份:2008
- 资助金额:
$ 36.23万 - 项目类别:
Prorenin Receptors Mediate Hypertension and Kidney Disease in Diabetes
肾素原受体介导糖尿病中的高血压和肾脏疾病
- 批准号:
8208167 - 财政年份:2008
- 资助金额:
$ 36.23万 - 项目类别:
Prorenin Receptor Mediates Early Changes in Diabetic Kidney
肾素原受体介导糖尿病肾脏的早期变化
- 批准号:
8512918 - 财政年份:2008
- 资助金额:
$ 36.23万 - 项目类别:
Prorenin Receptors Mediate Hypertension and Kidney Disease in Diabetes
肾素原受体介导糖尿病中的高血压和肾脏疾病
- 批准号:
7745451 - 财政年份:2008
- 资助金额:
$ 36.23万 - 项目类别:
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