Sex disparities in aldosterone-dependent renal Na+ transport and blood pressure control
醛固酮依赖性肾钠转运和血压控制的性别差异
基本信息
- 批准号:10461199
- 负责人:
- 金额:$ 39.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-03 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAddressAdultAffectAlbuminuriaAldosteroneAldosterone AntagonistsAmilorideAngiotensin IIAnimal ModelAnimalsAntihypertensive AgentsAreaAttenuatedAutomobile DrivingBlood PressureCardiovascular DiseasesCardiovascular systemCessation of lifeChronicClinicalDataDevelopmentDiseaseDistalDoseEquilibriumExcretory functionExhibitsFemaleFunctional disorderGenomicsGonadal Steroid HormonesHumanHypersensitivityHypertensionInflammationInfusion proceduresInjury to KidneyInterventionInvestigationKidneyKidney DiseasesKnowledgeLinkMeasuresMediatingMicroscopyMineralocorticoid ReceptorMolecularMusNatriuretic PeptidesNephronsOutcomePathogenicityPathologyPathway interactionsPatient NoncompliancePatientsPopulationProductionPublic HealthQuantitative Reverse Transcriptase PCRRandomizedRattusReceptor InhibitionRegulationRiskRodentSafetySex DifferencesSignal TransductionSodiumTestingTherapeuticTreatment EfficacyWestern BlottingWomanantagonistartery infusionbiological sexblood pressure controlblood pressure elevationblood pressure reductionblood pressure regulationcardiovascular risk factorclinically relevantcohortcombatdecubitus ulcerepithelial Na+ channelexperimental studyfemale sex hormonehypertension treatmenthypertensiveimprovedinhibitormalemenmodifiable risknon-genomicnovelpre-clinicalprematurereceptor expressionrenal arteryrenal damagerenal epitheliumresponsereuptakesalt sensitivesexsex disparitytreatment strategy
项目摘要
Hypertension remains a major public health challenge worldwide despite the abundance of available therapeutic
options. Inappropriate therapy and patient non-compliance are the main factors accounting for poor blood
pressure (BP) control. Identification of the mechanisms responsible for elevation of BP in specific patient cohorts
is critical to effectively combat hypertension and related diseases. Excessive sodium retention via the Epithelial
Na• Channel (ENaC) hampers the ability of the kidney to make precise adjustments to sodium balance and is a
common pathogenic determinant of hypertension. Cumulative evidence suggests that biological sex is a
pivotal covariate affecting the development and pathophysiology of hypertension in the human population and
animal models. Our proposal introduces a novel concept that regulation of Na• reabsorption in the kidney and
renal BP control rely on sex-specific mechanisms governing ENaC activity in the aldosterone-sensitive distal
nephron. We and others have previously shown that aldosterone antagonism with mineralocorticoid receptor
(MR) inhibitors is insufficient to reduce excessive renal ENaC activity and fails to effectively attenuate BP in male
rodents with angiotensin II (Angil) dependent hypertension. Our pilot experiments reveal that hypertensive
female rats with salt-sensitive and Angil-dependent hypertension benefit from MR antagonism and exhibit a
stronger BP reduction, when compared to males. MR blockade is also much more potent at decreasing renal
ENaC activity in Ang II-infused female rats than in males. Our findings strongly suggest that sensitivity of renal
ENaC to aldosterone is an unrecognized sex-specific mechanism of chronic BP regulation. The proposal is
built around the central hypothesis that hypersensitivity of ENaC to aldosterone accounts for a prevalent
contribution of aldosterone to renal BP control in hypertensive female rats, when compared to males. We propose
to test the hypothesis with two complementary specific aims addressing a clinically relevant problem of adequate
blood pressure control at the molecular, cellular {Aim 1) and integrative {Aim 2) levels. Aim 1 will test the
hypothesis that sensitivity of renal ENaC to aldosterone is greater in hypertensive female rats than in males. Our
hypothesis predicts that female sex steroids positively modulate MR-dependent signaling in the kidney to
augment the response of ENaC to aldosterone in hypertensive females. Aim 2 will test the hypothesis that
aldosterone dominates renal BP control in hypertensive female, but not in male, rats. Our hypothesis predicts
that aldosterone-MR axis is the primary driver of hypertension and renal damage in females and MR antagonism
will be dramatically more effective at reducing BP and renal injury in hypertensive females than in males.
Successful completion of this proposal will differentiate the pathophysiological mechanisms governing Na•
retention in hypertensive males and females and provide the missing pre-clinical evidence to optimize the
use of MR antagonists in hypertensive patients of both sexes.
尽管有大量可用的治疗方法,高血压仍然是世界范围内的一个主要公共卫生挑战
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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Mykola Mamenko其他文献
Mykola Mamenko的其他文献
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{{ truncateString('Mykola Mamenko', 18)}}的其他基金
Sex disparities in aldosterone-dependent renal Na+ transport and blood pressure control
醛固酮依赖性肾钠转运和血压控制的性别差异
- 批准号:
10682559 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
Sex disparities in aldosterone-dependent renal Na+ transport and blood pressure control
醛固酮依赖性肾钠转运和血压控制的性别差异
- 批准号:
10298925 - 财政年份:2021
- 资助金额:
$ 39.52万 - 项目类别:
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