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.

摘要 高血压（HTN）与交感神经系统活动（SNA）增加有关， 肾传出神经的活动被认为是重要的。然而，肾脏也受肾脏神经支配。 传入神经，其投射到中枢神经系统回路，该中枢神经系统回路调节SNA到各种外周 目标的因此，也假定增加的传入肾神经活动（ARNA）有助于增加的肾功能。 SNA和HTN的发病机制。现在，用于治疗人类HTN的肾去神经支配（RDNx）是一种新的治疗方法。 可能然而，RDNx降低AP的机制仍然未知。一种新兴的 HTN可能会提供新的见解。据推测，HTN是由以下因素的密切关系引起的： 肾神经、肾脏炎症和HTN。这些结果表明，抗高血压反应， RDNx不是由于肾功能的神经控制本身的破坏，而是由于阻断了 免疫细胞与传出和传入肾神经。 这些发现导致了这一提议的中心假设：DOCA盐HTN部分由以下因素引起： 促炎细胞因子对传入肾神经的作用导致神经源性介导的HTN。 四个具体目标将严格检验这一中心假设。具体目标1：调查 细胞因子调节DOCA盐大鼠ARNA的神经生理机制。具体目标二： 定义DOCA-盐大鼠中负责免疫介质调节ARNA的解剖学底物 和老鼠。具体目标3：关联介导抗高血压反应的血流动力学机制 DOCA-盐HTN中ARNA的消融和药理学阻断，肾脏疾病的尿生物标志物 炎症具体目的4：采用新型GCaMP 3小鼠离体肾切片制备物来鉴定 介导正常和DOCA-盐小鼠中传入肾神经的细胞因子调节的分子靶点。 在HTN中，免疫细胞与肾传入神经相互作用的机制的鉴定也将 有助于了解SNA升高的其他肾脏炎症性疾病，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

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

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

Reply from V. A. Averina, H. G. Othmer, G. D. Fink and J. W. Osborn.

V. A. Averina、H. G. Othmer、G. D. Fink 和 J. W. Osborn 的答复。

• DOI: 10.1113/jphysiol.2013.254607
• 发表时间: 2013
• 期刊: The Journal of physiology
• 作者: Averina,ViktoriaA;Othmer,HansG;Fink,GregoryD;Osborn,JohnW
• 通讯作者: Osborn,JohnW