Novel Roles of Mitochondrial Angiotensin II in The Proximal Tubule of The Kidney
线粒体血管紧张素 II 在肾近端小管中的新作用
基本信息
- 批准号:9765283
- 负责人:
- 金额:$ 20.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2004
- 资助国家:美国
- 起止时间:2004-03-01 至 2020-02-29
- 项目状态:已结题
- 来源:
- 关键词:AGTR2 geneAdultAgonistAngiotensin IIAntihypertensive AgentsAttenuatedBiological MarkersBlood PressureCCL2 geneCardiovascular DiseasesCardiovascular systemCell NucleusCell surfaceCellsChimeric ProteinsClinical TrialsCongestive Heart FailureCyclic GMPDrug TargetingElectronsEndosomesFemaleFundingGenetic TranscriptionGenus HippocampusGlycolysisGrantHypertensionImpairmentIn VitroKidneyKidney DiseasesKidney FailureKnockout MiceLDL-Receptor Related Protein 2LeftLiver MitochondriaMediatingMicroinjectionsMicroscopic AutoradiographyMitochondriaMusNADPH OxidaseNational Institute of Diabetes and Digestive and Kidney DiseasesNatriuresisNuclearOralPathogenesisPathway interactionsPatientsPlayProximal Kidney TubulesReceptor SignalingRegulationRenin-Angiotensin SystemReportingResolutionRoleSignal PathwaySignal TransductionStressStrokeSubgroupTestingTissuesUnited Statesacetovanilloneadenoviral-mediatedblood pressure reductionblood pressure regulationcaveolin 1extracellularmalemitochondrial dysfunctionmultiphoton imagingnoveloverexpressionpressurepromoterprotective effectreceptorrespiratoryresponse
项目摘要
In the United States, one in three adults will develop hypertension and require antihypertensive treatments in
their lifetime. Yet only 1/2 of hypertensive patients respond to current antihypertensive drugs, and 1/3 of
hypertensive patients will continue to develop cardiovascular and renal complications. The mechanisms
underlying poorly controlled hypertension in response to current antihypertensive therapies remain
incompletely understood. Supported by NIDDK grants, we have established that: 1) circulating and tissue ANG
II is taken up by the proximal tubule (PT) via AT1a receptor-, the endocytic receptor megalin-, or caveolin 1-
dependent mechanisms; 2) internalized ANG II and AT1 (AT1a) receptors are localized in the endosomes and
nuclei of PT cells; 3) intracellular microinjection of ANG II increases [Ca ]i, whereas exposure of freshly
2+
isolated renal cortical nuclei with ANG II induces transcriptional TGF-β1, MCP-1, and the Na+/H+ exchanger 3
(NHE3) responses via AT1a receptors; 4) in vitro or intrarenal adenovirus-mediated overexpression of an
intracellular ANG II fusion protein with AT1a receptors selectively in the PT induces NHE3 expression, promotes
Na+ reabsorption, and increases blood pressure, and 5) global- or kidney-selective deletion of NHE3 attenuates
ANG II-induced hypertension. These studies strongly suggest that intracellular ANG II may play an important
role in the regulation of Na+ transport in the PT and blood pressure homeostasis. In this A1 revised proposal,
we will test a new hypothesis that in the PT of the kidney, ANG II and AT1 (AT1a) are internalized into the
mitochondria, where mito-ANG II exerts dual roles on the mitochondrial function via activation of the
AT1a/Ca2+/NADPH oxidase/O2.- and the AT2/eNOS/NO/cGMP signaling pathways. Activation of the AT1a/
Ca2+/NADPH oxidase/O2.- pathway induces mitochondrial respiratory and glycolysis stress, impairs
pressure natriuresis response, and increases blood pressure, whereas activation of the mitochondrial
AT2/eNOS/NO/cGMP pathway by ANG II promotes pressure natriuresis and lowers blood pressure. In
Aim 1, we will use high resolution electron microscopic autoradiography and intravital multiphoton imaging to
determine whether AT1 (AT1a) and AT2 receptors are localized in the mitochondria of the PT, and whether [125I]-
ANG II or Alexa 488®-ANG II is internalized into the mitochondria of the PT in mice. In Aim II, we will determine
whether overexpression of a mitochondria-targeting mito-ANG II in PT cells impairs mitochondrial function by
activating the AT1a/Ca2+/NADPH oxidase/O2.- signaling pathways, whereas overexpression of mito-AT2R
protects mitochondrial function by activating the AT2/eNOS/NO/cGMP signaling. The PT-specific sglt2 promoter
and the mitochondria-targeting sequence will be used to drive the overexpression of mito-ANG II, mito-AT1aR or
mito-AT2R in PT cells. In Aim III, we will determine whether activation of mito-AT1aR by mito-ANG II in the PT
induces mitochondrial respiratory and glycolysis stress, impairs pressure natriuresis responses, and increases
blood pressure using specific PT-AT1a-KO, PT-AT2-KO, PT-NHE3-KO, or PT-SIRT3-KO mice, respectively.
在美国,三分之一的成年人会患高血压并需要抗高血压治疗
他们的一生。然而,只有 1/2 的高血压患者对当前的抗高血压药物有反应,1/3 的患者
高血压患者将继续出现心血管和肾脏并发症。机制
对当前抗高血压治疗的潜在高血压控制不佳的情况仍然存在
不完全理解。在 NIDDK 拨款的支持下,我们已经确定:1) 循环和组织 ANG
II 通过 AT1a 受体、内吞受体巨蛋白或小窝蛋白 1- 被近端小管 (PT) 吸收
依赖机制; 2) 内化的 ANG II 和 AT1 (AT1a) 受体位于核内体中,并且
PT细胞的细胞核; 3)细胞内显微注射ANG II会增加[Ca ]i,而新鲜的暴露
2+
分离的肾皮质核与 ANG II 诱导转录 TGF-β1、MCP-1 和 Na+/H+ 交换器 3
(NHE3) 通过 AT1a 受体作出反应; 4) 体外或肾内腺病毒介导的过表达
细胞内 ANG II 融合蛋白与 AT1a 受体选择性地在 PT 诱导 NHE3 表达,促进
Na+ 重吸收,血压升高,5) NHE3 的整体或肾脏选择性缺失会减弱
ANG II 诱发的高血压。这些研究强烈表明细胞内 ANG II 可能发挥重要作用
PT 和血压稳态中 Na+ 转运的调节作用。在此 A1 修订提案中,
我们将测试一个新的假设,即在肾脏的 PT 中,ANG II 和 AT1 (AT1a) 内化到肾脏的 PT 中。
线粒体,mito-ANG II 通过激活线粒体对线粒体功能发挥双重作用
AT1a/Ca2+/NADPH 氧化酶/O2.- 和 AT2/eNOS/NO/cGMP 信号通路。 AT1a/的激活
Ca2+/NADPH 氧化酶/O2.- 途径诱导线粒体呼吸和糖酵解应激,损害
压力尿钠反应,并增加血压,而线粒体的激活
ANG II 的 AT2/eNOS/NO/cGMP 通路可促进压力尿钠排泄并降低血压。在
目标1,我们将使用高分辨率电子显微镜放射自显影和活体多光子成像
确定 AT1 (AT1a) 和 AT2 受体是否位于 PT 的线粒体中,以及是否 [125I]-
ANG II 或 Alexa 488®-ANG II 内化至小鼠 PT 的线粒体中。在目标 II 中,我们将确定
PT 细胞中线粒体靶向 mito-ANG II 的过度表达是否会通过以下方式损害线粒体功能:
激活 AT1a/Ca2+/NADPH 氧化酶/O2.- 信号通路,而 mito-AT2R 过度表达
通过激活 AT2/eNOS/NO/cGMP 信号传导来保护线粒体功能。 PT 特异性 SGLT2 启动子
线粒体靶向序列将用于驱动 mito-ANG II、mito-AT1aR 或
PT 细胞中的 mito-AT2R。在目标 III 中,我们将确定 PT 中 mito-ANG II 是否激活 mito-AT1aR
诱导线粒体呼吸和糖酵解应激,损害压力尿钠反应,并增加
分别使用特定的 PT-AT1a-KO、PT-AT2-KO、PT-NHE3-KO 或 PT-SIRT3-KO 小鼠测量血压。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jia L. Zhuo其他文献
Recent Advances in Understanding the Molecular Pathophysiology of Angiotensin II Receptors: Lessons From Cell-Selective Receptor Deletion in Mice
理解血管紧张素Ⅱ受体分子病理生理学的最新进展:来自小鼠细胞选择性受体缺失的经验教训
- DOI:
10.1016/j.cjca.2023.06.421 - 发表时间:
2023-12-01 - 期刊:
- 影响因子:5.300
- 作者:
Satoru Eguchi;Matthew A. Sparks;Hisashi Sawada;Hong S. Lu;Alan Daugherty;Jia L. Zhuo - 通讯作者:
Jia L. Zhuo
The Na+/H+ exchanger 3 in the proximal tubule of the kidney as a novel mechanism of pressure natriuresis responses and angiotensin ii-induced hypertension
- DOI:
10.1016/j.jash.2016.03.157 - 发表时间:
2016-04-01 - 期刊:
- 影响因子:
- 作者:
Xiao C. Li;Manoocher Soleimani;Hoang Nguyen;Jia L. Zhuo - 通讯作者:
Jia L. Zhuo
Jia L. Zhuo的其他文献
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{{ truncateString('Jia L. Zhuo', 18)}}的其他基金
Intratubular Angiotensin II and AT1a Receptors in The Proximal Tubules: Roles in Hypertension and Kidney Injury
近曲小管中的管内血管紧张素 II 和 AT1a 受体:在高血压和肾损伤中的作用
- 批准号:
10164776 - 财政年份:2020
- 资助金额:
$ 20.81万 - 项目类别:
Novel Roles of Mitochondrial Angiotensin II in The Proximal Tubule of The Kidney
线粒体血管紧张素 II 在肾近端小管中的新作用
- 批准号:
10251271 - 财政年份:2020
- 资助金额:
$ 20.81万 - 项目类别:
Novel Roles of Mitochondrial Angiotensin II in The Proximal Tubule of The Kidney
线粒体血管紧张素 II 在肾近端小管中的新作用
- 批准号:
10174147 - 财政年份:2020
- 资助金额:
$ 20.81万 - 项目类别:
Intratubular Angiotensin II and AT1a Receptors in The Proximal Tubules: Roles in Hypertension and Kidney Injury
近曲小管中的管内血管紧张素 II 和 AT1a 受体:在高血压和肾损伤中的作用
- 批准号:
10398943 - 财政年份:2020
- 资助金额:
$ 20.81万 - 项目类别:
Intratubular Angiotensin II and AT1a Receptors in The Proximal Tubules: Roles in Hypertension and Kidney Injury
近曲小管中的管内血管紧张素 II 和 AT1a 受体:在高血压和肾损伤中的作用
- 批准号:
10627786 - 财政年份:2020
- 资助金额:
$ 20.81万 - 项目类别:
Role of Proximal Tubule NHE3 in Angiotensin II-induced Hypertension
近曲小管 NHE3 在血管紧张素 II 诱导的高血压中的作用
- 批准号:
10174160 - 财政年份:2017
- 资助金额:
$ 20.81万 - 项目类别:
The Na+/H+ Exchanger 3, Pressure Natriuresis, and Hypertension
Na /H 交换器 3、压力尿钠和高血压
- 批准号:
9336432 - 财政年份:2016
- 资助金额:
$ 20.81万 - 项目类别:
Role of Proximal Tubule NHE3 in Angiotensin II-induced Hypertension
近曲小管 NHE3 在血管紧张素 II 诱导的高血压中的作用
- 批准号:
8742716 - 财政年份:2014
- 资助金额:
$ 20.81万 - 项目类别:
Role of Intracrine Angiotensin II in Kidney Cells
内分泌血管紧张素 II 在肾细胞中的作用
- 批准号:
7193516 - 财政年份:2004
- 资助金额:
$ 20.81万 - 项目类别:
Role of Intracrine Angiotensin II in Kidney Cells
内分泌血管紧张素 II 在肾细胞中的作用
- 批准号:
6761389 - 财政年份:2004
- 资助金额:
$ 20.81万 - 项目类别:
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