Renal Sensory Nerve Contribution to Hypertension

肾感觉神经对高血压的影响

基本信息

批准号：
10670924
负责人：
Bryan K Becker
金额：
$ 16.17万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2021-08-27 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670924
关键词：
Adenosine Affect Afferent Neurons Angiotensin II Animals Applications Grants Blood Pressure Cardiovascular Diseases Chemicals Chronic Chronic Kidney Failure Clinical Clinical Research Conscious Data Denervation Development Devices Disease Electrophysiology (science)Endothelin Endothelin A Receptor Endothelin B Receptor Endothelin-1 Equilibrium Fatty acid glycerol esters Foundations Functional disorder Future Goals High Fat Diet Hypertension Image In Vitro Intervention Kidney Label Mechanics Mediating Mentors Modeling Morbidity - disease rate Natriuresis Nerve Neurons Pathway interactions Peptides Physiology Play Population Population Heterogeneity Rattus Receptor Activation Receptor Signaling Reflex action Renal pelvis Reporting Research Proposals Rodent Model Role Sensory Sodium Sodium Chloride Spinal Ganglia Stimulus Stretching Sympathetic Nervous System System Technical Expertise Techniques Testing Therapeutic Intervention Training Tubular formation Uncertainty Water afferent nerve autonomic nerve desensitization diet-induced obesity dietary experience experimental study hemodynamics high salt diet hypertension treatment instrument kidney vascular structure mortality novel patch clamp pharmacologic receptor receptor expression research study response salt sensitive salt sensitive hypertension success targeted delivery therapeutic target western diet

Adenosine Affect Afferent Neurons Angiotensin II Animals Applications Grants Blood Pressure Cardiovascular Diseases Chemicals Chronic Chronic Kidney Failure Clinical Clinical Research Conscious Data Denervation Development Devices Disease Electrophysiology (science)Endothelin Endothelin A Receptor Endothelin B Receptor Endothelin-1 Equilibrium Fatty acid glycerol esters Foundations Functional disorder Future Goals High Fat Diet Hypertension Image In Vitro Intervention Kidney Label Mechanics Mediating Mentors Modeling Morbidity - disease rate Natriuresis Nerve Neurons Pathway interactions Peptides Physiology Play Population Population Heterogeneity Rattus Receptor Activation Receptor Signaling Reflex action Renal pelvis Reporting Research Proposals Rodent Model Role Sensory Sodium Sodium Chloride Spinal Ganglia Stimulus Stretching Sympathetic Nervous System System Technical Expertise Techniques Testing Therapeutic Intervention Training Tubular formation Uncertainty Water afferent nerve autonomic nerve desensitization diet-induced obesity dietary experience experimental study hemodynamics high salt diet hypertension treatment instrument kidney vascular structure mortality novel patch clamp pharmacologic receptor receptor expression research study response salt sensitive salt sensitive hypertension success targeted delivery therapeutic target western diet

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项目摘要

PROJECT SUMMARY/ABSTRACT: High blood pressure is a leading cause of morbidity and mortality worldwide and greatly contributes to a multitude of cardiovascular disease. Although the renal sympathetic nerves have been the focus of many basic and clinical studies, the role of the renal afferent (sensory) nerves in mediating hypertension remains poorly understood. Activation of renal afferents can potentially either excite or inhibit global sympathetic nerve activity and thereby increase or decrease blood pressure, but the precise mechanisms controlling the balance of the excitatory vs. inhibitory reflex actions of the renal afferent nerves are currently unknown. We have recently determined that the endothelin-1 (ET-1) system significantly modulates renal afferent nerves. Our central hypothesis is that endothelin A (ETA) receptor activation on renal afferent nerves increases sympathetic nerve activity and blood pressure, and that endothelin B (ETB) receptor activation on renal afferent nerves decreases sympathetic nerve activity and blood pressure. We will test this hypothesis using rodent models in the settings of both normal physiology and hypertension. ETA or ETB receptors on renal nerves will be directly activated in rats instrumented with radiotelemetry devices, which allow for recording of blood pressure and markers of sympathetic nerve activity in unrestrained, conscious animals. These experiments, which will also include in vitro culturing, imaging, and electrophysiological examination of renal afferent nerves will provide important new information about the mechanisms of afferent nerve activation. High salt and high fat content are common features of the typical Western diet and are well-known to play a role in the development of many cardiovascular diseases such as hypertension. Our preliminary evidence indicates that these factors also increase renal afferent nerve expression of ET-1 and ETA receptors. Because of this connection to increases in abberant renal afferent nerve activity and blood pressure, we will also test the hypothesis that high salt or high fat diet increases afferent nerve ET-1 expression and a preponderance of ETA to ETB receptor signaling promoting increased afferent nerve activity, sympathetic tone, and blood pressure. This hypothesis will be tested through the use of rat models with specific pharmacological inhibition of ETA and/or ETB receptors on renal afferent nerves, and animals will be fed a high salt or high fat diet. Together, these studies will provide a mechanistic understanding of how excitation versus inhibition of renal afferent nerves contributes to hypertension and thus could lead to specific and efficient therapeutic interventions for the treatment of hypertension. This research study and the proposed mentored training plan will provide the applicant with the specific scientific training needed for successful transition into independence.

项目摘要/摘要：高血压是全球发病率和死亡率的主要原因，并大大促成多种心血管疾病。虽然肾同情神经一直是许多基本的重点和临床研究，肾脏传入（感觉）神经在介导高血压中的作用仍然很差理解。肾脏传入的激活可能会激发或抑制全局交感神经活动从而增加或降低血压，但控制着平衡的精确机制目前尚不清楚肾脏传入神经的兴奋性与抑制性反射作用。我们最近有确定内皮素-1（ET-1）系统显着调节肾脏传入神经。我们的中心假设是肾脏神经上的内皮素A（ETA）受体激活会增加交感神经神经活性和血压，以及肾脏传入的内皮素B（ETB）受体激活神经降低交感神经活动和血压。我们将使用啮齿动物检验此假设正常生理和高血压的设置中的模型。肾神经上的ETA或ETB受体将是直接在用辐射电子仪器仪器的大鼠中激活，这允许记录血压和不受约束的有意识的动物中交感神经活动的标志。这些实验将还包括体外培养，成像和肾脏神经的电生理检查有关传入神经激活机制的重要新信息。高盐和高脂肪含量是典型的西方饮食的常见特征，众所周知在许多心血管疾病（例如高血压）的发展中发挥作用。我们的初步证据表明这些因素还增加了ET-1和ETA受体的肾脏传入神经表达。因为这是与增加宽大肾脏传入的神经活动和血压增加的联系，我们还将测试假设高盐或高脂肪饮食会增加传入的神经ET-1表达和优势 ETA对ETB受体信号的传导促进传入神经活动，交感神经和血液的增加压力。该假设将通过使用具有特定药理抑制的大鼠模型来检验在肾脏神经上的ETA和/或ETB受体的含量，将喂养高盐或高脂肪饮食。这些研究将共同对激发与抑制的机理理解肾脏传入神经有助于高血压，因此可能导致特定有效的治疗治疗高血压的干预措施。这项研究和拟议的指导培训计划将向申请人提供成功过渡到独立性所需的特定科学培训。