Afferent renal nerves, renal inflammation, and hypertension

传入肾神经、肾脏炎症和高血压

• 批准号: 10308480
• 负责人: John W Osborn
• 金额: $ 51.12万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308480
• 关键词: Ablation; Anatomy; Antihypertensive Agents; Attenuated; Biological Markers; Biological Response Modifiers; Brain; Catheters; Cells; Chronic Kidney Failure; Clinical; Clinical Trials; Conduct Clinical Trials; DOCA; Denervation; Development; Diagnostic tests; Diastolic blood pressure; Disease; Drug Targeting; Drug resistance; Efferent Neurons; Failure; Follow-Up Studies; Human; Hypertension; Immune; Inflammation; Inflammatory; Inflammatory Response; Kidney; Laboratories; Link; Maintenance; Mediating; Methods; Molecular Target; Morbidity - disease rate; Mus; Nerve; Neuraxis; Pathogenesis; Patients; Pelvis; Peripheral; Pharmacology; Phase; Physiological; Preparation; Rat-1; Rattus; Renal function; Research; Role; Slice; Sodium Chloride; Sympathetic Nervous System; Systolic Pressure; T-Lymphocyte; Testing; Training; Translations; United States; Urine; afferent nerve; base; cytokine; diagnostic biomarker; hemodynamics; hypertension treatment; hypertensive; insight; mortality; neurophysiology; neuroregulation; new therapeutic target; normotensive; novel; pressure; public health relevance; response; salt sensitive hypertension; theories; translational barrier; treatment response; trial design; urinary

Abstract Hypertension (HTN) is linked to increased sympathetic nervous system activity (SNA) and increased activity of renal efferent nerves is thought to be important. However, the kidneys are also innervated by renal afferent nerves, which project to central nervous system circuits that modulate SNA to various peripheral targets. As such, increased afferent renal nerve activity (ARNA) is also postulated to contribute to increased SNA and the pathogenesis of HTN. Renal denervation (RDNx) for treatment of HTN in humans is now possible. However, the mechanisms by which RDNx lowers AP remain unknown. An emerging new theory of HTN may provide new insights. It is hypothesized that HTN is caused, in part, by a close relationship between renal nerves, renal inflammation, and HTN. These findings suggest that the antihypertensive response to RDNx is not due to disruption of neural control of renal function per se, but rather, blockade of the interaction of immune cells with efferent and afferent renal nerves. These findings led to the Central Hypothesis of this proposal: DOCA-salt HTN is caused, in part, by the action of proinflammatory cytokines on afferent renal nerves resulting in neurogenically mediated HTN. Four Specific Aims will rigorously test this Central Hypothesis. Specific Aim 1: Investigate the neurophysiological mechanisms by which cytokines modulate ARNA in the DOCA-salt rat. Specific Aim 2: Define the anatomical substrates responsible for modulation of ARNA by immune mediators in DOCA-salt rats and mice. Specific Aim 3: Correlate the hemodynamic mechanisms mediating the anti-hypertensive response to ablation and pharmacological blockade of ARNA in DOCA-salt HTN, to urinary biomarkers of renal inflammation. Specific Aim 4: Employ a novel GCaMP3 mouse ex vivo renal slice preparation to identify molecular targets mediating cytokine modulation of afferent renal nerves in normal and DOCA-salt mice. Identification of the mechanisms by which immune cells interact with renal afferent nerves in HTN will also benefit understanding other renal inflammatory diseases with elevated SNA such as chronic renal failure.

抽象的 高血压（HTN）与交感神经系统活动增加（SNA）有关 肾脏传出神经的活性被认为很重要。但是，肾脏也被肾脏支配 传入神经，这些神经投射到中枢神经系统电路，将SNA调节到各种周围 目标。因此，还假设增加的传入肾神经活动（ARNA）有助于增加 SNA和HTN的发病机理。现在，用于人类HTN治疗的肾脏去神经（RDNX）现在为 可能的。但是，RDNX降低AP的机制仍然未知。新兴的新理论 HTN可能会提供新的见解。假设HTN是由于一定程度地造成的 肾神经，肾脏炎症和HTN。这些发现表明对 RDNX不是由于肾功能本身的神经控制的破坏，而是封锁的相互作用 具有传出和传入的肾神经的免疫细胞。 这些发现导致了该提议的中心假设：Doca-Salt HTN是由 促炎细胞因子对传入肾神经的作用，导致神经源介导的HTN。 四个具体目标将严格检验此中心假设。特定目标1：调查 神经生理机制通过这些机制调节DOCA-盐大鼠中ARNA的神经生理机制。具体目标2： 定义负责通过DOCA-SALT大鼠免疫介质调节ARNA的解剖基板 和老鼠。特定目的3：将介导抗高血压反应的血流动力学机制相关联 在DOCA-SALT HTN中消融和药理学阻滞，到肾脏的尿生物标志物 炎。特定目的4：采用新型的GCAMP3小鼠外体肾切片制剂来识别 分子靶标在正常和DOCA盐小鼠中介导传入肾神经的细胞因子调节。 鉴定免疫细胞与HTN中肾脏传入神经相互作用的机制也将 受益于了解其他肾脏炎症性疾病，具有升高的SNA，例如慢性肾衰竭。

项目成果

Renal nerves: time for reassessment of their role in hypertension?

肾神经：是时候重新评估其在高血压中的作用了？

• DOI: 10.1093/ajh/hpu096
• 发表时间: 2014
• 期刊: American journal of hypertension
• 影响因子: 3.2
• 作者: Fink,GregoryD;Osborn,JohnW
• 通讯作者: Osborn,JohnW

OVLT lesion decreases basal arterial pressure and the chronic hypertensive response to AngII in rats on a high-salt diet.

• DOI: 10.1002/phy2.128
• 发表时间: 2013-10
• 期刊: PHYSIOLOGICAL REPORTS
• 影响因子: 2.5
• 作者: Collister, John P;Olson, Marin K;Nahey, David B;Vieira, Alexandre A;Osborn, John W
• 通讯作者: Osborn, John W

Targeting the sympathetic nervous system: critical issues in patient selection, efficacy, and safety of renal denervation.

• DOI: 10.1161/hypertensionaha.113.02144
• 发表时间: 2014-03
• 期刊: Hypertension
• 影响因子: 8.3
• 作者: M. Schlaich;M. Esler;G. Fink;J. Osborn;D. Euler

Response to more research is needed to investigate the effect of denervation on blood pressure.

需要进行更多研究来调查去神经支配对血压的影响。

• DOI: 10.1161/hypertensionaha.114.03055
• 发表时间: 2014
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Schlaich,Markus;Esler,Murray;Fink,Greg;Osborn,John;Euler,David
• 通讯作者: Euler,David

Role of afferent and efferent renal nerves in the development of AngII-salt hypertension in rats.

• DOI: 10.14814/phy2.13602
• 发表时间: 2018-03
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Foss JD;Fiege J;Shimizu Y;Collister JP;Mayerhofer T;Wood L;Osborn JW
• 通讯作者: Osborn JW