Evaluating the Mechanisms of Afferent Renal Nerve Ablation as a Treatment for Hypertension

评估传入肾神经消融治疗高血压的机制

基本信息

批准号：
10604700
负责人：
Arthur Trenton de la Cruz-Lynch
金额：
$ 3.99万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10604700
关键词：
Ablation Acetates Address Aftercare Anatomy Antihypertensive Agents Applications Grants Biological Markers Blood Pressure Blood Volume Brain CXCL10 gene CXCR3 gene Capsaicin Cardiac Output Cardiovascular Diseases Catheters Cells Chronic Clinical Clinical Trials Deoxycorticosterone Disease Doctor of Philosophy Drug resistance Echocardiography Efferent Neurons Ensure Enzyme-Linked Immunosorbent Assay Ethanol Foundations Functional disorder Future Goals Harvest Hemorrhagic Shock Human Hypertension IL17 gene Immune Immunohistochemistry Implant Inflammation Inflammatory Interleukin-1 alpha Intervention Kidney Laboratories Life Style Modification Liver Measurement Measures Methods Modeling Monitor Nerve Nervous System Operative Surgical Procedures Organ Output Patients Peripheral Pharmaceutical Preparations Physicians Physiological Plasma Play Pre-Clinical Model Property Rattus Reporting Research Resistance Resistant Hypertension Rodent Rodent Model Role Saline Sampling Scientist Sensory Septic Shock Sheep Spleen TNF gene Technology Testing Therapeutic Translating Translational Research Treatment Efficacy Tunica Adventitia Urine afferent nerve blood pressure reduction blood pressure regulation cardiovascular risk factor chemokine clinically relevant clinically significant comparative efficacy cytokine experimental study heart function hemodynamics high salt diet hypertension treatment insight minimally invasive neuroregulation neurotransmission novel novel therapeutics preservation pressure renal artery response sheep model skills success telemetering transmission process urinary

项目摘要

PROJECT SUMMARY/ABSTRACT Hypertension (HTN) is one of the most important risk factors for cardiovascular disease. Nearly half of HTN patients are resistant or nonadherent to lifestyle modification and drug-based therapy, so novel therapies are desperately needed. While HTN is associated with increased global sympathetic nerve activity, renal efferent nerves have traditionally been the focus of research since they transmit sympathetic nerve impulses from the brain to regulate blood pressure. However, the kidneys are also innervated by renal afferent (sensory) nerves, which project to circuits in the brain that modulate sympathetic nerve output and cause HTN. Clinical trials using catheter-based total (efferent and afferent) renal nerve ablation (TRDN) have been shown to effectively lower arterial pressure in treatment-resistant HTN patients. Despite this intervention’s efficacy, it is unknown if ablation of the efferent or afferent renal nerves is more important in lowering arterial pressure. To elucidate the role that afferent renal nerves play in HTN, our laboratory developed a novel method of afferent renal nerve ablation (ARDN) and found that ARDN was as effective as TRDN in decreasing arterial pressure in the deoxycorticosterone acetate and high salt diet (DOCA-salt) induced HTN rodent model. Clinically, if ARDN can lower arterial pressure to the same degree as TRDN, efferent renal nerves could be preserved to maintain blood pressure and volume in response to hemorrhagic or septic shock. Furthermore, TRDN has shown variable efficacy in certain patients, and the lack of biomarkers to predict the arterial pressure response to TRDN is a major gap in the field. Recent studies from our lab suggest that the presence of specific inflammatory cytokines in the urine can identify renal inflammation. These cytokines can overstimulate afferent renal nerves and cause increased global sympathetic nerve output and HTN. I plan on translating our findings from DOCA-salt HTN rodents to the DOCA-salt HTN sheep model. The anatomic, physiologic, and hemodynamic properties of HTN sheep more closely resemble human pathophysiology and allows for the use of human TRDN catheters. Therefore, the overall goal of this proposal is to develop and validate a catheter-based ARDN method using the HTN sheep model to address current gaps in the field and move closer to a clinical therapeutic for hypertension. Our central hypothesis is that catheter-based ARDN will decrease arterial pressure to the same degree as TRDN, and the arterial pressure response to TRDN can be predicted by specific urinary markers of renal inflammation. I will test this hypothesis with the following aims: (1) Compare the efficacy of catheter-based ARDN versus TRDN in an established model of HTN in sheep. (2) Validate the utility of urinary biomarkers to measure renal inflammation associated with HTN to predict the anti-HTN efficacy of TRDN. If successful, the results of the proposed studies will provide a translational platform to subsequently move into clinical trials of catheter-based ARDN in humans. Furthermore, this catheter-based neuromodulation approach can also be applied to other organs (liver, spleen) in which chronic inflammation drives other neurogenically based diseases.

项目概要/摘要高血压（HTN）是心血管疾病最重要的危险因素之一。患者对生活方式改变和药物治疗有抵抗力或不依从，因此新的疗法虽然 HTN 与整体交感神经活动增加有关，但肾传出神经活动增加。神经传统上一直是研究的焦点，因为它们从神经传递交感神经冲动然而，肾脏也受肾传入（感觉）神经支配，投射到大脑中调节交感神经输出并导致 HTN 的电路。基于导管的总（传出和传入）肾神经消融术（TRDN）已被证明可以有效降低尽管这种干预措施有效，但消融是否有效尚不清楚。传出或传入肾神经的作用在降低动脉压方面更为重要。传入肾神经在HTN中发挥作用，我们实验室开发了传入肾神经消融的新方法 (ARDN) 并发现 ARDN 在降低动脉压方面与 TRDN 一样有效临床上，如果ARDN可以，醋酸脱氧皮质酮和高盐饮食（DOCA-盐）诱导HTN啮齿动物模型。将动脉压降低到与 TRDN 相同的程度，可以保留传出肾神经以维持血液此外，TRDN 表现出对失血性或感染性休克的反应变化。 TRDN 在某些患者中的疗效不佳，并且缺乏预测动脉压对 TRDN 反应的生物标志物我们实验室最近的研究表明特定炎症细胞因子的存在。尿液中的细胞因子可以识别肾脏炎症。这些细胞因子会过度刺激肾传入神经并导致肾炎症。增加了整体交感神经输出和 HTN，我计划转化我们从 DOCA-salt HTN 中得到的发现。 DOCA-盐 HTN 绵羊模型的啮齿动物 HTN 的解剖学、生理学和血流动力学特性。绵羊的病理生理学更接近人类的病理生理学，并且允许使用人类 TRDN 导管。因此，本提案的总体目标是开发和验证基于导管的 ARDN 方法，使用 HTN 绵羊模型旨在解决该领域当前的空白，并更接近高血压的临床治疗。我们的中心假设是基于导管的 ARDN 可以将动脉压降低到与 TRDN 相同的程度， TRDN 的动脉压反应可以通过肾脏炎症的特定尿液标志物来预测。我将通过以下目标来检验这一假设：(1) 比较基于导管的 ARDN 与 TRDN 的疗效在已建立的绵羊 HTN 模型中 (2) 验证尿液生物标志物测量肾脏的效用。与HTN相关的炎症可预测TRDN的抗HTN功效。如果成功，则结果为TRDN。拟议的研究将提供一个转化平台，以便随后进入基于导管的临床试验此外，这种基于导管的神经调节方法也可以应用于其他领域。慢性炎症导致其他神经源性疾病的器官（肝脏、脾脏）。