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

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上高血压,需要抗高血压治疗。 他们的一生。然而,只有1/2的高血压患者对目前的降压药物有反应,1/3的高血压患者对目前的降压药物有反应。 高血压患者会继续出现心血管和肾脏并发症。的机制 对当前抗高血压治疗反应不佳的潜在高血压仍然存在 不完全理解。在NIDDK基金的支持下,我们已经确定:1)循环和组织ANG II通过AT 1a受体-、内吞受体megalin-或小窝蛋白1-被近端小管(PT)摄取。 依赖性机制; 2)内化的ANG II和AT 1(AT 1a)受体定位于内体, PT细胞核; 3)细胞内微量注射ANG II可增加[Ca] i,而暴露新鲜 2个以上 具有ANG II的分离的肾皮质核诱导TGF-β 1、MCP-1和Na +/H+交换器3的转录 (NHE3)通过AT1a受体的应答; 4)体外或肾内腺病毒介导的NHE3的过表达, 在PT中选择性地具有AT 1a受体的细胞内ANG II融合蛋白诱导NHE 3表达,促进 Na+重吸收,并增加血压,和5)整体或肾脏选择性缺失NHE3减弱 血管紧张素II诱导的高血压。这些研究强烈提示细胞内ANG II可能在细胞内的凋亡中起重要作用。 在PT和血压稳态中调节Na+转运的作用。在这份A1修订提案中, 我们将测试一个新的假设,即在肾脏PT中,ANG II和AT 1(AT 1a)被内化到 线粒体,其中mito-ANG II通过激活线粒体的线粒体功能发挥双重作用。 AT1a/Ca2 +/NADPH氧化酶/O2. - AT2/eNOS/NO/cGMP信号通路。激活AT1a/ Ca2 +/NADPH氧化酶/O2. -途径诱导线粒体呼吸和糖酵解应激, 血压升高,而线粒体的激活, 血管紧张素Ⅱ介导的AT2/eNOS/NO/cGMP通路促进压力性尿钠排泄,降低血压。在 目的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AT 1(AT 1a)和AT 2受体是否位于PT的线粒体中,以及[125 I]- ANG II或Alexa 488®-ANG II被内化到小鼠PT的线粒体中。在目标II中,我们将确定 PT细胞中靶向线粒体的ANG II的过表达是否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的过度表达 通过激活AT2/eNOS/NO/cGMP信号通路保护线粒体功能。PT特异性sglt2启动子 并且所述靶向线粒体的序列将用于驱动线粒体-ANG II、线粒体-AT1aR或 PT细胞中的mito-AT2R。在目的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,损害压力尿钠排泄反应,并增加 血压,分别使用特定的PT-AT1a-KO、PT-AT2-KO、PT-NHE3-KO或PT-SIRT3-KO小鼠。

项目成果

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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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