MECHANISMS AND ACTIONS OF H2O2 PRODUCTION IN THE mTAL OF THE DAHL S RAT
DAHL S 大鼠脑中 H2O2 产生的机制和作用
基本信息
- 批准号:8726473
- 负责人:
- 金额:$ 43.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AccountingAnimalsAutomobile DrivingBackBiological ModelsBlood PressureBlood flowCell membraneComputersCoupledDahl Hypertensive RatsDiffuseDiffusionEpithelial CellsEventExhibitsFeedsFluorescent ProbesFumarate HydrataseFumaric acidGenesGenetic EngineeringHomeostasisHydrogen PeroxideHypertensionImageInfiltrationInjuryIntakeKidneyKnowledgeLeadLimb structureMalignant - descriptorMalignant HypertensionMediatingMitochondriaMolecularNADPH OxidaseNitric OxideOrganPerfusionPericytesPhasePlayProcessProductionProtocols documentationRattusRectumRegulationRenal HypertensionRenal functionResearchResistanceRoleSignal TransductionSignaling MoleculeSodiumSodium ChlorideStagingSuperoxidesSystemT-LymphocyteTechniquesTestingThickTissuesTransgenic OrganismsTubular formationWhole Organismantioxidant therapyblood pressure regulationcellular imagingdesignenzyme pathwayfeedingfluorescence imagingfluorophoreinhibitor/antagonistinterstitialkidney medullaneutrophil cytosol factor 67Knew therapeutic targetnovelnovel strategiesnull mutationoverexpressionpressureprotein expressionresponsesalt intakesalt sensitivesalt sensitive hypertensionvasoconstriction
项目摘要
Superoxide and nitric oxide production within the outer medulla (OM) of the kidney are known to play
an important role in sodium homeostasis and in salt-sensitive hypertension and renal injury. Little is yet known
about the highly reactive H2O2 molecule which is involved in these processes and may account for as much as
50% of the hypertension and renal injury observed in the Dahl salt-sensitive (SS) rat. We hypothesize that
increased NaCI delivery to the medullary thick ascending limb (mTAL) of the OM, as occurs following an
increase in NaCI intake, stimulates mitochondrial production of H2O2 in the mTAL epithelial cells that diffuses to
the cell membrane and enhances the activity of NADPH oxidase leading to an overall increase of cellular levels
of H2O2 (Aim 1). We propose that this H2O2 response is significantly amplified in SS rats by greater expression
of the p67phox cytosolic subunit of NADPH oxidase compared to a salt-resistant control strain as explored in
Aim 2. The contribution of p67phox to these events will be determined ufilizing SS rats with a ubiquitous null
mutation in the p67phox gene and salt-resistant SS.13BN26 rats with mTAL-specific transgenic overexpression of
p67phox. In Aim 3, studies will determine if the greater production of H2O2 in the mTAL of SS rats results in
diffusion of H2O2 into the interstitial space of the surrounding vasa recta which results in pericyte-mediated
vasoconstriction and reduction of medullary blood flow leading to the initial moderate rise of arterial pressure.
Aim 4 will determine if the rise of blood pressure with salt intake provokes renal T-lymphocyte infiltration,
excess p67phox and fumaric acid in the mTAL leading to greater H2O2 production and a progression from a mild
to severe form of hypertension and renal injury. This is a highly collaborative protocol between Projects 1, 2
and 3 that will utilize a computer-controlled system to examine the consequences of the elevated renal
perfusion pressure by protecfing one kidney from the hypertension while the other is exposed to the elevated
blood pressure.
Since technical limitations have impeded a thorough mechanistic understanding of the role of H2O2 in
renal function and hypertension, a number of new fluorescent imaging approaches, a novel fluorescent probe
that specifically detects mitochondrial changes of H2O2, and a novel inhibitor of mitochondrial H2O2 will be
utilized to advance our understanding of this field. Several novel genetically engineered rat model systems
have been developed to test several of the key hypotheses including an SS rat with a ubiquitous null mutation
in the p67phox gene and a salt-insensitive SS.13BN26 in which p67phox is transgenically overexpressed only in the
thick ascending limb of Henle. H2O2 appears to be an important signaling molecule in the OM of the kidney. If
more effective antioxidant therapies are to be developed it will require knowledge of the expression and
regulation of the key pathways and enzymes responsible for H2O2 formation and their functional relevance at
the level of the tissue and whole organism. By identifying the two novel controllers of H2O2 production, one
related to the mitochondria and the other to the p67phox gene, we anticipate identifying new therapeutic targets
for hypertension.
超氧化物和一氧化氮的产生在肾脏的外髓质(OM)中起作用。
在钠稳态和盐敏感性高血压和肾损伤中起重要作用。目前所知甚少
关于参与这些过程的高活性H2O2分子,可能占
在Dahl盐敏感(SS)大鼠中观察到50%的高血压和肾损伤。我们假设
向OM的髓厚升支(mTAL)输送的NaCl增加,如在
NaCl摄入量的增加,刺激mTAL上皮细胞中线粒体产生H2O2,
细胞膜,并增强NADPH氧化酶的活性,导致细胞水平的总体增加
H2O2(目标1)。我们认为,这种H2O2反应在SS大鼠中被显著放大,
NADPH氧化酶的p67phox胞质亚基与耐盐对照菌株相比,如
目标2. p67phox对这些事件的贡献将通过使用普遍存在的空表达的SS大鼠来确定。
p67phox基因突变和耐盐SS.13BN 26大鼠与mTAL特异性转基因过表达的
p67phox。在目标3中,研究将确定SS大鼠mTAL中H2O2的更大产生是否导致
H2O2扩散到周围直小血管的间隙中,导致周细胞介导的
血管收缩和髓血流量减少,导致动脉压最初适度升高。
目的4将确定血压升高与盐摄入是否引起肾脏T淋巴细胞浸润,
mTAL中过量的p67 phox和富马酸导致更大的H2O2产生,并且从温和的
严重的高血压和肾损伤。这是项目1、2之间的高度协作协议
和3将利用计算机控制的系统来检查肾功能升高的后果,
通过保护一个肾脏免受高血压,而另一个肾脏暴露于升高的灌注压,
血压.
由于技术限制阻碍了对H2O2在生物体内作用的彻底的机械理解,
肾功能和高血压,一些新的荧光成像方法,一种新的荧光探针
特异性检测线粒体H2O2的变化,一种新的线粒体H2O2抑制剂将被发现。
用来增进我们对这一领域的了解。几种新的基因工程大鼠模型系统
已经被开发来测试几个关键假设,包括具有普遍无效突变的SS大鼠
13BN 26,其中p67phox仅在p67phox基因中转基因过表达。
Henle的粗的上升肢。H2O2似乎是肾脏OM中的重要信号分子。如果
要开发更有效的抗氧化剂疗法,就需要了解其表达,
负责H2O2形成的关键途径和酶的调节及其功能相关性,
组织和整个生物体的水平。通过识别H2O2生产的两个新控制器,
另一个与p67phox基因相关,我们期待找到新的治疗靶点
治疗高血压
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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Allen W Cowley其他文献
Allen W Cowley的其他文献
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{{ truncateString('Allen W Cowley', 18)}}的其他基金
Experimental and computational analysis of mechanisms of mitochondrial-cellular ROS crosstalk in the kidney in salt-sensitive hypertension
盐敏感性高血压肾脏线粒体-细胞 ROS 串扰机制的实验和计算分析
- 批准号:
10529290 - 财政年份:2021
- 资助金额:
$ 43.29万 - 项目类别:
Experimental and computational analysis of mechanisms of mitochondrial-cellular ROS crosstalk in the kidney in salt-sensitive hypertension
盐敏感性高血压肾脏线粒体-细胞 ROS 串扰机制的实验和计算分析
- 批准号:
10321663 - 财政年份:2021
- 资助金额:
$ 43.29万 - 项目类别:
How Can Precision Medicine be Applied to Temporomandibular Disorders and its Comorbidities?
精准医学如何应用于颞下颌关节疾病及其合并症?
- 批准号:
9193954 - 财政年份:2016
- 资助金额:
$ 43.29万 - 项目类别:
Role of NOX4 In Kidney Function In Salt-Sensitive Hypertension
NOX4 在盐敏感性高血压肾功能中的作用
- 批准号:
8886255 - 财政年份:2015
- 资助金额:
$ 43.29万 - 项目类别:
Role of NOX4 In Kidney Function In Salt-Sensitive Hypertension
NOX4 在盐敏感性高血压肾功能中的作用
- 批准号:
9444474 - 财政年份:2015
- 资助金额:
$ 43.29万 - 项目类别:
Genetics and Epigenetics - Temporomandibular Disorders and Related Overlapping Co
遗传学和表观遗传学 - 颞下颌疾病和相关重叠疾病
- 批准号:
8785556 - 财政年份:2014
- 资助金额:
$ 43.29万 - 项目类别:
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