Renal Sensory Nerve Contribution to Hypertension

肾感觉神经对高血压的影响

• 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
• 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

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： 高血压是全世界发病率和死亡率的主要原因，并在很大程度上导致 多种心血管疾病。尽管肾交感神经一直是许多基础研究的焦点 临床研究表明，肾传入(感觉神经)在调节高血压中的作用仍然很差。 明白了。激活肾传入神经可潜在地兴奋或抑制全局交感神经活动 从而提高或降低血压，但控制血压平衡的精确机制 肾传入神经的兴奋性或抑制性反射作用目前尚不清楚。我们最近做了 确定内皮素-1(ET-1)系统对肾传入神经有显著的调节作用。我们的中央 假设肾传入神经上的内皮素A(ETA)受体激活可增加交感神经 肾传入神经活动与血压及内皮素B受体激活的关系 神经会降低交感神经活性和血压。我们将用啮齿动物来验证这一假说 在正常生理和高血压两种情况下的模型。肾神经上的ETA或ETB受体将 在装有无线电遥测设备的大鼠身上直接激活，允许记录血压 以及无拘无束、有意识的动物的交感神经活动的标记。这些实验，将会 还包括肾传入神经的体外培养、成像和电生理检查 关于传入神经激活机制的重要新信息。 高盐和高脂肪是典型的西式饮食的共同特征，众所周知 在高血压等许多心血管疾病的发展中起着重要作用。我们的初步证据 提示这些因素也增加了肾传入神经ET-1和ETA受体的表达。因为 关于这种与肾传入神经活动和血压增加的联系，我们还将测试 高盐或高脂饮食增加传入神经ET-1表达的假设及其优势 ETA到ETB受体信号促进传入神经活性、交感神经张力和血液的增加 压力。这一假说将通过使用具有特定药物抑制作用的大鼠模型来验证 肾脏传入神经上的ETA和/或ETB受体，动物将被喂以高盐或高脂肪饲料。 总之，这些研究将提供一种机制上的理解，即兴奋与抑制是如何 肾传入神经有助于高血压，从而可能导致特异性和有效的治疗。 治疗高血压的干预措施。这项研究研究和拟议的指导性培训计划将 为申请人提供成功过渡到独立所需的具体科学培训。