Structural and functional neurobiology of renal nerves: A platform for neuromodulation of renal function

肾神经的结构和功能神经生物学：肾功能神经调节平台

• 批准号: 9770836
• 负责人: John W Osborn
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770836
• 关键词: Ablation; Address; Afferent Neurons; Anatomy; Animals; Argipressin; Basic Science; Blood Vessels; Body Fluids; Cardiovascular Physiology; Cardiovascular system; Catheters; Chemicals; Chronic; Clinical Research; Conscious; Development; Devices; Diabetes Mellitus; Disease; Dose; Efferent Neurons; Electric Stimulation; Glomerular Filtration Rate; Homeostasis; Human; Hypertension; Inflammation; Kidney; Knowledge; Laboratories; Maintenance; Maps; Mechanics; Methodology; Methods; Mus; Nerve; Neuraxis; Neurobiology; Neuropeptides; Patients; Pelvis; Physiological; Physiology; Play; Renal function; Renal pelvis; Renin; Reporting; Research; Role; Secondary to; Skeletal Muscle; Sleep Apnea Syndromes; Sodium; Stimulus; Structure; TRPV1 gene; Testing; Time; Tissues; Transgenic Mice; Translations; Tubular formation; afferent nerve; base; capsaicin receptor; constriction; design; effective therapy; experimental study; glucose metabolism; hypertension treatment; improved; mouse model; nerve supply; neurochemistry; neurophysiology; neuroregulation; novel; optogenetics; pressure; relating to nervous system; response; targeted treatment; treatment response; voltage

Project Summary Design of neuromodulatory devices targeting the kidney requires detailed knowledge of the structural and functional neurobiology of renal nerves. Our current understanding is fairly rudimentary and based on classical but outdated methodologies. For example, it is generally agreed that renal efferent nerves increase renin release, stimulate sodium reabsorption, and decrease GFR secondary to arteriolar constriction. However, the dose-response relationships for these effects are based on supramaximal electrical stimulation of renal nerves in anesthetized animals. Recent studies in conscious animals suggest this dogma may be incorrect. Even less is known regarding the structural and functional neurobiology of renal afferent nerves. Although it is well accepted that the renal pelvic wall in densely innervated, preliminary findings in our laboratory, as well as reports by others, suggest sensory nerves may also innervate vascular and tubular targets throughout the kidney. However, the physiological role of renal afferent nerves is unclear. Finally, it is well established that the afferent and efferent innervation of the kidney is heterogeneous. Distinct subsets of sympathetic renal nerves express the neuropeptides NPY and VIP. In the afferent renal innervation there is partial overlap of expression of the neuropeptides CGRP and SP and the capsaicin receptor TRPV1. In addition, our preliminary results demonstrate for the first time the presence of renal afferent nerves that express the sensory neuron-specific voltage-gated Na+ channel NaV1.8. The functional significance of the neurochemical diversity of renal afferent and efferent nerves represents a critical gap in our understanding of neural control of kidney function. Our central hypothesis is that efferent and afferent nerves with distinct neurochemical signatures differentially control renal functions through their association with distinct renal structures. We will use state-of- the-art neurophysiological and neuroanatomical approaches to generate an integrated functional and structural map of neural control in the mouse kidney. We will also initiate translation of these finding to the human kidney through comprehensive neuroanatomical analysis. In Specific Aim 1 will test the hypothesis that neurochemically distinct renal nerves differentially control renal function. In Specific Aim 2 we will test the hypothesis that neurochemically distinct renal nerves are associated with distinct structures in the kidney. Finally, in Specific Aim 3 we will define the structural neurobiology of renal efferent and afferent nerves, and their relationship to vascular, tubular and renal pelvis anatomy in the human kidney.

项目概要 针对肾脏的神经调节装置的设计需要详细的结构知识 和肾神经的功能神经生物学。我们目前的理解还相当初级，并且基于 经典但过时的方法论。例如，人们普遍认为肾传出神经增加 肾素释放，刺激钠重吸收，并降低继发于小动脉收缩的 GFR。然而， 这些效应的剂量-反应关系基于肾脏的超最大电刺激 麻醉动物的神经。最近对有意识的动物的研究表明，这种教条可能是不正确的。 关于肾传入神经的结构和功能神经生物学知之甚少。虽然它是 我们实验室的初步发现以及肾盂壁神经支配密集这一点已被广泛接受 其他人的报告表明，感觉神经也可能在整个过程中支配血管和管状目标 肾。然而，肾传入神经的生理作用尚不清楚。最后，众所周知， 肾脏的传入和传出神经支配是异质的。肾交感神经的不同亚群 表达神经肽NPY和VIP。在传入肾神经支配中存在部分表达重叠 神经肽 CGRP 和 SP 以及辣椒素受体 TRPV1。此外，我们的初步结果 首次证明表达感觉神经元特异性的肾传入神经的存在 电压门控 Na+ 通道 NaV1.8。肾传入神经化学多样性的功能意义 传出神经代表了我们对肾功能神经控制理解的一个关键差距。 我们的中心假设是传出神经和传入神经具有不同的神经化学特征 通过与不同肾脏结构的关联来差异控制肾功能。我们将使用状态- 最先进的神经生理学和神经解剖学方法来生成集成的功能和结构 小鼠肾脏的神经控制图。我们还将开始将这些发现转化为人类肾脏 通过全面的神经解剖学分析。在具体目标 1 中，将检验以下假设： 神经化学上不同的肾神经不同地控制肾功能。在具体目标 2 中，我们将测试 假设神经化学上不同的肾神经与不同的结构有关 肾。最后，在具体目标 3 中，我们将定义肾传出神经和传入神经的结构神经生物学 神经及其与人体肾脏血管、肾小管和肾盂解剖结构的关系。

项目成果

Periglomerular afferent innervation of the mouse renal cortex.

小鼠肾皮质的肾小球周围传入神经支配。

• 发表时间: 2023
• 作者: Tyshynsky, Roman;Sensarma, Sulagna;Riedl, Maureen;Bukowy, John;Schramm, Lawrence P;Vulchanova, Lucy;Osborn, John W
• 通讯作者: Osborn, John W