Redox control of medullary function and blood pressure
髓质功能和血压的氧化还原控制
基本信息
- 批准号:7367207
- 负责人:
- 金额:$ 30.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-03-01 至 2008-02-28
- 项目状态:已结题
- 来源:
- 关键词:7,8-dihydrobiopterinAntioxidantsArginineBackBiological AvailabilityBlood PressureBlood VesselsBlood flowBuffersChemicalsChromosomes, Human, Pair 13ChronicConsomic StrainCoupledDahl Hypertensive RatsDataDevelopmentDietElevationEnzyme UncouplingEnzymesEpithelial CellsEquilibriumExcretory functionExhibitsFeedsFluorescent DyesFunctional disorderGenerationsGenomicsGoalsHigh Pressure Liquid ChromatographyHomeostasisHumanHydrogen PeroxideHydrostatic PressureHydroxyl RadicalHypertensionHypochlorous AcidHypochlorous AcidsImageInbred Dahl RatsIndividualInfusion proceduresInterventionKidneyLeadLocalizedMeasurementMessenger RNAMicrodialysisMicroscopicModalityModelingNADH oxidaseNatriuresisNitric OxideNitric Oxide PathwayNorwayNumbersOxidantsOxidation-ReductionOxidative StressPeroxonitritePlayProductionRattusReactive Nitrogen SpeciesReactive Oxygen SpeciesRegulationRenal Blood FlowRenal functionReverse Transcriptase Polymerase Chain ReactionRoleSodiumSodium ChlorideSodium-Restricted DietSourceSpeedStressSuperoxidesTechniquesTimeTissuesTubular formationWaterclinically relevantconceptconsomicextracellularin vivointerstitialkidney medullanovelnovel therapeuticsparacrinepressureprogramsresponsesalt sensitivetetrahydrobiopterinvasoconstriction
项目摘要
The overall goal of this project is to advance our understanding of the role that reactive oxygen species (ROS) and reactive nitrogen species (RNS) play in determining renal function, especially that of the renal medulla, a region that is vulnerable to excess O2- production. We have previously established that changes in renal medullary blood flow play an important role in sodium homeostasis and the long-term regulation of arterial pressure and shown
that nitric oxide (NO) production plays a key role in the regulation of blood flow to this region. We hypothesize that excess production of ROS in the renal medulla reduces NO bioavailability, lowers medullary blood flow, increases tubular sodium reabsorption and results in a salt-sensitive form of hypertension. This project, as all others in this PPG, utilizes Dahl salt-sensitive rats that are genetically defined (SS/Mcw) and a newly developed consomic control strain derived from the inbred SS/Mcw strain in which chromosome 13 from the salt-insensitive BN/Mcw strain has been introgressed into the genomic background of the SS/Mcw rat (SS.BN13 consomic strain). This consomic SS.BN13 strain is 98% identical to the SS/Mcw strain but is relatively salt-insensitive. Aim 1 will determine if the renal medulla of Dahl salt-sensitive rats (SS/Mcw) produces excess ROS (O2, H2O2, ONOO) that feeds back to
uncouple nitric oxide syntheses enzymes (NOS) and reduce the redo ratio of tetrahydrobiopterin (BH4)/dihydrobiopterin (BH2) (i.e., a vicious cycle of O2. production). Newly developed fluorescent microdialysis and HPLC analytical techniques will enable comparison of ROS and NO pathways in salt-sensitive (SS/Mcw) and in salt-insensitive consomic SS.BN13 rats. Our preliminary data indicate that this control strain exhibits significantly lower levels of medullary ROS. Studies will also determine whether lowering of ROS in the medulla of SS/Mcw
rats by chronic medullary infusion of antioxidants increases medullary blood flow and reduces salt-induced hypertension. Aim 2 will determine the effects of induced medullary elevations of ROS in salt-insensitive SS.BN13 consomic rats. Medullary blood flow, renal interstitial hydrostatic pressure (RIHP), arterial pressure (AP) and the pressure-natriuresis relationships will be determined in response to chronic elevations of O2-, H2O2, and ONOO-. The concept of NOS uncoupling will be examined by measurement of medullary tissue BH4/BH2 ratios determined
by HPLC, and NO, O2 and H2O2 values obtained by microdialysis techniques. Aim 3 will determine the dynamic inter-relationships of O2 and NO within and between vascular and tubular segments of the renal medulla using thin, superfused medullary tissue stripes. NO responses to agents that stimulate and inhibit ROS will be compared in control SS.BN13 and salt-sensitive SS/Mcw rats. Novel fluorescent dyes, coupled with high speed capture of microscopic images will enable the measurement of intracellular NO independent from NO in the interstitial space thereby determining whether NO released from tubules could act as a paracrine substance to control medullary blood flow. Taken together, these studies will provide novel and clinically relevant data defining the role that ROS play in the regulation of renal medullary function and the development of salt-sensitive hypertension, information that would be expected to lead to new therapeutic modalities in the treatment of human hypertension.
本项目的总体目标是促进我们对活性氧(ROS)和活性氮(RNS)在决定肾功能中所起作用的理解,特别是肾髓质,这是一个容易产生过量O2的区域。我们先前已经证实,肾髓质血流的变化在钠稳态和动脉压的长期调节中起重要作用,
一氧化氮(NO)的产生在调节流向该区域的血液中起关键作用。我们推测肾髓质中ROS的过量产生降低了NO的生物利用度,降低了髓质血流量,增加了肾小管钠重吸收,并导致盐敏感型高血压。与本PPG中的所有其他项目一样,本项目使用遗传定义的Dahl盐敏感大鼠(SS/Mcw)和一种新开发的同源对照品系,该品系来源于近交SS/Mcw品系,其中盐不敏感BN/Mcw品系的13号染色体已渗入SS/Mcw大鼠的基因组背景(SS. BN 13同源品系)。该同源体SS.BN13菌株与SS/Mcw菌株具有98%的同一性,但相对盐不敏感。目的1将确定Dahl盐敏感大鼠(SS/Mcw)的肾髓质是否产生过量的ROS(O2,H2 O2,ONOO),其反馈到
解偶联一氧化氮合成酶(NOS)并降低四氢生物蝶呤(BH 4)/二氢生物蝶呤(BH 2)的还原比率(即,氧气的恶性循环生产)。新开发的荧光微透析和HPLC分析技术将能够比较盐敏感(SS/Mcw)和盐不敏感的consomic SS. BN 13大鼠的ROS和NO途径。我们的初步数据表明,该对照菌株表现出显着较低水平的髓ROS。研究还将确定SS/Mcw髓质中ROS的降低是否
大鼠通过慢性髓内灌注抗氧化剂增加了髓血流量并降低了盐诱导的高血压。目的2将确定在盐不敏感的SS. BN 13 consomic大鼠中诱导的延髓ROS升高的影响。将根据O2-、H2 O2和ONOO-的慢性升高确定髓质血流量、肾间质静水压力(RIHP)、动脉压(AP)和压力-尿钠排泄关系。NOS解偶联的概念将通过测量髓组织的BH 4/BH 2比率来检查,
通过HPLC测定NO、O2和H2 O2值。目的3将使用薄的,灌流的髓质组织条纹来确定在肾髓质的血管和管状段内和之间的O2和NO的动态相互关系。将在对照SS.BN13和盐敏感性SS/Mcw大鼠中比较NO对刺激和抑制ROS的试剂的应答。新的荧光染料,加上高速捕获的显微图像将能够测量细胞内NO独立于NO在间隙空间,从而确定是否从小管释放NO可以作为旁分泌物质来控制髓血流量。总之,这些研究将提供新的和临床相关的数据,定义的作用,活性氧在肾髓质功能的调节和盐敏感性高血压的发展,信息,预计将导致新的治疗方式在治疗人类高血压。
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:
$ 30.25万 - 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:
$ 30.25万 - 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:
$ 30.25万 - 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:
$ 30.25万 - 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:
$ 30.25万 - 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:
$ 30.25万 - 项目类别:
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