Renal Denervation To Treat Hypertension: Mechanisms and Mediators

肾去神经术治疗高血压：机制和介质

• 批准号: 10226255
• 负责人: Christopher T Banek
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-06 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226255
• 关键词: Abate; Ablation; Acute; Adult; Antihypertensive Agents; Argipressin; Attenuated; Blood Pressure; Brain; CCL2 gene; Cardiovascular Diseases; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Cutaneous; DOCA; Data; Denervation; Development; Efferent Neurons; Epidemic; Etiology; Excretory function; Human; Hypertension; Immune; Infiltration; Inflammation; Inflammatory; Injections; Interleukin-1 beta; Interleukin-6; Kidney; Kidney Diseases; Laboratories; Link; Measures; Mediating; Mediator of activation protein; Methodology; Methods; Modeling; Morbidity - disease rate; Nephritis; Nerve; Peripheral; Play; Population; Pre-Clinical Model; Prevention; Rattus; Reflex action; Regulation; Renin; Research; Residual state; Rest; Role; Signal Transduction; Sodium; Sodium Chloride; Sympathetic Nervous System; T-Lymphocyte; Techniques; Testing; United States; Vascular resistance; afferent nerve; blood pressure regulation; cardiovascular risk factor; clinical application; cytokine; experimental study; high risk; hypertension treatment; in vivo; macrophage; mortality; nerve supply; neuroregulation; neurotransmission; new therapeutic target; normotensive; novel; novel therapeutics; preclinical study; pressure; prevent; response; salt sensitive hypertension; targeted treatment; therapeutic target; trafficking

PROJECT SUMMARY: High blood pressure (hypertension; HTN) continues at epidemic levels in the United States. Though HTN etiology remains debated, the kidney remains a key contributor to blood pressure control. Moreover, elevated sympathetic nerve activity (SNA) and innervation of the kidney is closely linked to BP control, through both efferent (signal from brain to kidney) and afferent (kidney to brain) nerve signaling. A large body of experimental and clinical studies demonstrates ablation of these nerves, or renal denervation (RDNx), can prevent and reverse HTN. Although this anti-HTN response is exciting, the mechanism by which RDNx treats HTN remains ill-defined. It remains unclear whether efferent (signal from brain to kidney; ERN) and afferent (kidney to brain; ARN) renal nerves populations differentially contribute to HTN. In general, ERNs regulate renin release, vascular resistance, and sodium excretion, whereas ARNs modulates arginine vasopressin (AVP) secretion and peripheral SNA. Renal nerves are known to interact with and influence renal inflammation (nephritis), which is posited to cause HTN. Consistent with these findings, our laboratory has recently demonstrated the antihypertensive response to RDNx may be due to the blockade of the interaction between inflammatory signaling and renal nerves. Specifically, we observed ablation of all renal nerves (T-RDNx; efferent+afferent) attenuated HTN and abolished renal inflammatory cytokines (e.g. IL-1β, IL-6, MCP-1) in the DOCA-salt rat model; however, selective ablation of ARNs (A-RDNx) only attenuated the HTN and not the cytokines. DOCA-salt HTN and nephritis was also paired with a 2.3-fold increase in resting afferent renal nerve activity (ARNA) compared to normotensive controls. In concert, these data suggest ERNs regulate inflammatory trafficking, and ARNs mediate the HTN in this model. With our previous observations and strong preliminary data outlined in this proposal, we formed the following testable Central Hypothesis: (a) Elevated renal SNA (RSNA) drives the infiltration of activated immune cells (e.g. T-cells, macrophage) which produce pro-inflammatory cytokines; (b) These cytokines activate or hypersensitize ARNs; (c) Increased ARNA reflexly raises peripheral SNA and AVP release, and, in turn, blood pressure. We will test this hypothesis with the following specific aims: (1) Asses the chronic renal SNA response to DOCA-salt, and the effect of afferent-specific denervation (A-RDNx). We will directly measure ARNA and renal SNA changes in parallel to blood pressure in the DOCA-salt rat. (2) Evaluate if renal inflammation alters renal afferent nerve activity and sensitivity. Using an established in vivo and a novel ex vivo method to acutely measure ARNA, we will determine if renal inflammatory cytokines increase resting ARNA. (3) Determine the role of afferent renal nerves in the regulation of the neurohumoral response to DOCA-salt. We will determine if A-RDNx blunts AVP secretion in the DOCA-salt HTN model. By defining the specific role of renal nerves in HTN and nephritis, we will fundamentally redefine the mechanistic basis for clinical use of RDNx and potentially identify therapeutic targets for the HTN treatment.

项目概要： 尽管高血压是高血压的病因，但在美国，高血压仍处于流行水平。 尽管仍存在争议，但肾脏仍然是血压控制的关键因素。 交感神经活动 (SNA) 和肾脏的神经支配与血压控制密切相关，通过两者 传出（从大脑到肾脏的信号）和传入（肾脏到大脑）神经信号传导的大量实验。 临床研究表明，消融这些神经或肾去神经术 (RDNx) 可以预防和逆转 尽管这种抗 HTN 反应令人兴奋，但 RDNx 治疗 HTN 的机制仍不明确。 目前尚不清楚传出信号（信号从大脑到肾脏；ERN）和传入信号（信号从肾脏到大脑；ARN）是否是肾信号 一般来说，ERN 调节肾素释放、血管阻力、 和钠排泄，而 ARN 调节精氨酸加压素 (AVP) 分泌和外周 SNA。 已知肾神经与肾脏炎症（肾炎）相互作用并影响肾脏炎症，这被认为会导致 与这些发现一致，我们的实验室最近证明了 HTN 的抗高血压反应。 RDNx可能是由于炎症信号传导与肾神经之间的相互作用被阻断所致。 具体来说，我们观察到所有肾神经（T-RDNx；传出神经+传入神经）的消融减弱了 HTN 并消除了 然而，DOCA盐大鼠模型中的肾脏炎症细胞因子（例如IL-1β、IL-6、MCP-1）是选择性消融的； ARN (A-RDNx) 仅减弱 HTN，而不减弱细胞因子 DOCA-盐 HTN 与肾炎也配对。 与正常血压对照相比，静息传入肾神经活动 (ARNA) 增加 2.3 倍。 总之，这些数据表明 ERN 调节炎症运输，而 ARN 在此模型中介导 HTN。 根据我们之前的观察和本提案中概述的强有力的初步数据，我们形成了以下内容 可检验的中心假设：(a) 肾 SNA (RSNA) 升高驱动激活的免疫细胞（例如免疫细胞）的浸润。 (b) 这些细胞因子激活或过敏 ARN；(c) ARNA 增加会反射性地提高外周 SNA 和 AVP 的释放，进而提高血压。 将通过以下具体目标检验这一假设：（1）评估 DOCA 盐的慢性肾脏 SNA 反应， 以及传入特异性去神经 (A-RDNx) 的影响 我们将直接测量 ARNA 和肾脏 SNA 的变化。 与 DOCA 盐大鼠的血压平行 (2) 评估肾脏炎症是否改变肾传入神经。 我们使用既定的体内方法和新颖的离体方法来精确测量 ARNA。 将确定炎症细胞因子是否增加静息肾 ARNA (3) 确定传入肾的作用。 我们将确定 A-RDNx 是否会减弱 AVP。 DOCA-盐 HTN 模型中的分泌 通过定义肾神经在 HTN 和肾炎中的具体作用，我们 将从根本上重新定义 RDNx 临床使用的机制基础，并可能确定治疗方法 HTN 治疗的目标。

项目成果

Sequential afferent and sympathetic renal denervation impact on cardiovascular and renal homeostasis in the male Sprague-Dawley rat.

顺序传入肾和交感肾去神经支配对雄性斯普拉格道利大鼠心血管和肾脏稳态的影响。

• 发表时间: 2023-07-15
• 影响因子: 6.1
• 作者: Parvin, Irin;Gauthier, Madeline M;Dennis, Melissa R;Encinas, Noah M;Nangia, Ellen L;Schwartz, Kyle L;Banek, Christopher T
• 通讯作者: Banek, Christopher T

Renal Denervation and Celiac Ganglionectomy Decrease Mean Arterial Pressure Similarly in Genetically Hypertensive Schlager (BPH/2J) Mice.

在遗传性高血压施拉格 (BPH/2J) 小鼠中，肾去神经支配和腹腔神经节切除术同样会降低平均动脉压。

• 发表时间: 2021
• 作者: Asirvatham;Gauthier, Madeline M;Banek, Christopher T;Ramesh, Abhismitha;Garver, Hannah;Fink, Gregory D;Osborn, John W
• 通讯作者: Osborn, John W

Contributions of afferent and sympathetic renal nerves to cystogenesis and arterial pressure regulation in a preclinical model of autosomal recessive polycystic kidney disease.

常染色体隐性多囊肾病临床前模型中传入肾和交感肾神经对囊肿发生和动脉压调节的贡献。

• 发表时间: 2022-06-01
• 作者: Gauthier, Madeline M;Dennis, Melissa R;Morales, Mark N;Brooks, Heddwen L;Banek, Christopher T
• 通讯作者: Banek, Christopher T

Renal Denervation Update From the International Sympathetic Nervous System Summit: JACC State-of-the-Art Review.

国际交感神经系统峰会的肾去神经更新：JACC 最先进的评论。

• DOI: 10.1016/j.jacc.2019.04.015
• 发表时间: 2019-06-18
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Kiuchi MG;Esler MD;Fink GD;Osborn JW;Banek CT;Böhm M;Denton KM;DiBona GF;Everett TH 4th;Grassi G;Katholi RE;Knuepfer MM;Kopp UC;Lefer DJ;Lohmeier TE;May CN;Mahfoud F;Paton JFR;Schmieder RE;Pellegrino PR;Sharabi Y;Schlaich MP
• 通讯作者: Schlaich MP

Lesion of the OVLT markedly attenuates chronic DOCA-salt hypertension in rats.

OVLT 损伤可显着减轻大鼠慢性 DOCA 盐高血压。

• 发表时间: 2018
• 作者: Collister, John P;Nahey, David B;Hartson, Rochelle;Wiedmeyer, Charles E;Banek, Christopher T;Osborn, John W
• 通讯作者: Osborn, John W