Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
心房钠尿肽在盐敏感性高血压中的线粒体介导作用和治疗潜力
基本信息
- 批准号:10472035
- 负责人:
- 金额:$ 52.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-14 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAdipose tissueAffectAnimal ModelAnimalsAntioxidantsAtrial Natriuretic FactorAttenuatedBioenergeticsBiogenesisBlood PressureBlood Pressure MonitorsCellsChronicClinicClinical DataCultured CellsCyclic GMPDahl Hypertensive RatsDataDefectDevelopmentDiseaseDiuresisDuct (organ) structureEchocardiographyElectrophysiology (science)Energy MetabolismEquilibriumEventExcretory functionExhibitsExperimental DesignsFree Radical FormationFunctional disorderGenerationsHeartHormonesHydrogen PeroxideImageImpairmentIndividualInfusion proceduresInjury to KidneyKidneyKnock-outKnowledgeLinkLocationMeasurementMediatingMetabolicMicroscopyMitochondriaMolecularMolecular BiologyMuscleNatriuretic PeptidesNephronsOrganPathologicPathway interactionsPeptide Signal SequencesPermeabilityPersonsPharmaceutical PreparationsPhenotypePilot ProjectsPlasmaProductionRattusReactive Oxygen SpeciesRegulationRenal Blood FlowRenal TissueResistanceRespirationSodiumSodium ChlorideSpin TrappingSuperoxidesTAC1 geneTechniquesTestingTherapeuticTherapeutic EffectTissuesVasodilationattenuationbaseblood flow measurementblood pressure controlblood pressure elevationblood pressure reductioncGMP productiondesigndietary salteffective therapyepithelial Na+ channelheart functionhigh riskhypertension treatmenthypertensiveimprovedin vivometabolic abnormality assessmentmitochondrial dysfunctionnovelpatch clamppatient subsetsreceptor sensitivityrecruitrenal damagesalt intakesalt sensitivesalt sensitive hypertensiontreatment strategy
项目摘要
PROJECT SUMMARY
There is no specific treatment available for the subpopulation of patients with salt sensitivity of blood pressure
(BP); unfortunately, the molecular mechanisms underlying salt-sensitivity remain poorly understood. One of the
major proposed mechanisms for the development of salt-sensitive (SS) hypertension involves a defect in the
ability of the kidneys to excrete salt. Atrial Natriuretic Peptide (ANP) encoded by Nppa, is a hormone known to
promote salt excretion and BP reduction, and there are clinical data implicating inherently low levels of ANP in
the development of SS hypertension. Among other effects, ANP (via cGMP-related mechanisms) is known to be
beneficial for mitochondrial bioenergetics and biogenesis. However, there is a gap in knowledge regarding the
effects of ANP on mitochondria in the kidney, especially in SS hypertension. Our pilot studies demonstrated
that during a high salt challenge Nppa-/- (ANP knockout) Dahl SS rats exhibit exacerbated salt-sensitivity,
reduced sodium excretion, and aggravated kidney injury, which is associated with mitochondrial damage and
dysfunction. We also showed that there is dysregulation of renal sodium transporters, in the Nppa-/- rats
compared to wild-type controls, and the activity of the Epithelial Na+ Channel (ENaC) is elevated in the collecting
ducts. Chronic ANP infusion in wild-type SS rats resulted in a dramatic attenuation of salt-induced BP increase
and alleviated organ damage.
We hypothesize that in SS hypertension ANP deficiency/reduced sensitivity to ANP is causative to renal
mitochondrial dysfunction and associated sodium transport imbalance. To address the central hypothesis of this
project, we developed three specific aims: Aim 1. Establish whether increased ANP levels are beneficial for
renal salt handling and cardiac function in SS hypertension. Aim 2. Determine whether low renal cGMP level
resulting from lack of ANP causes an increase in renal mitochondrial Ca2+ and reactive oxygen species (ROS).
Aim 3. Test the hypothesis that disrupted Ca2+ balance and excessive ROS production by dysfunctional
mitochondria affect renal sodium handling in SS hypertension.
We generated abundant evidence to support these aims, created a rigorous and comprehensive experimental
design and established novel cutting-edge techniques to address the hypothesis. We recruited strong
collaborative expertise, and will implement a combination of whole-animal studies and in vivo techniques (blood
pressure monitoring with drug infusion, metabolic studies and GFR measurements), electrophysiology (single
channel and whole-cell patch-clamp of the freshly isolated nephrons and isolated mitochondria), advanced
microscopy, mitochondrial spectrofluorimetry and respirometry, and routine molecular biology approaches. The
successful completion of the proposed studies will unravel the novel causative mechanisms of salt-sensitivity.
项目总结
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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Daria Ilatovskaya其他文献
Daria Ilatovskaya的其他文献
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{{ truncateString('Daria Ilatovskaya', 18)}}的其他基金
Improving awareness of women with hypertension: ROAR (Rural, Obese, At Risk) Career Enhancement Core
提高女性高血压患者的意识:ROAR(农村、肥胖、高危)职业提升核心
- 批准号:
10714535 - 财政年份:2023
- 资助金额:
$ 52.54万 - 项目类别:
Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
心房钠尿肽在盐敏感性高血压中的线粒体介导作用和治疗潜力
- 批准号:
10676800 - 财政年份:2020
- 资助金额:
$ 52.54万 - 项目类别:
Mitochondria-mediated effects and therapeutic potential of Atrial Natriuretic Peptide in salt-sensitive hypertension
心房钠尿肽在盐敏感性高血压中的线粒体介导作用和治疗潜力
- 批准号:
10442162 - 财政年份:2020
- 资助金额:
$ 52.54万 - 项目类别:
Mitochondria-Mediated Effects and Therapeutic Potential of Atrial Natriuretic Peptide in Salt-Sensitive Hypertension Diversity Supplement
盐敏感性高血压多样性补充剂中心房钠尿肽的线粒体介导作用和治疗潜力
- 批准号:
10337412 - 财政年份:2020
- 资助金额:
$ 52.54万 - 项目类别:
The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis
ENaC 的 ATP 依赖性抑制参与 ARPKD 囊肿发生
- 批准号:
10419229 - 财政年份:2018
- 资助金额:
$ 52.54万 - 项目类别:
The involvement of ATP-dependent inhibition of ENaC in ARPKD cystogenesis
ENaC 的 ATP 依赖性抑制参与 ARPKD 囊肿发生
- 批准号:
9146873 - 财政年份:2015
- 资助金额:
$ 52.54万 - 项目类别:
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