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

项目摘要 针对肾脏的神经调节装置的设计需要详细的结构知识 肾神经的功能神经生物学。我们目前的理解是相当初级的，是基于 经典但过时的方法。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，减少继发于小动脉收缩的GFR。然而， 这些效应的剂量-反应关系是基于对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进行的研究表明，这一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更是知之甚少。尽管它是 我们实验室的初步发现表明，肾盆壁有密集的神经支配。 其他人的报告表明，感觉神经也可能支配血管和管状靶点。 肾脏。然而，肾传入神经的生理作用尚不清楚。最后，众所周知， 肾的传入和传出神经分布是不同的。交感肾神经的不同亚群 表达神经肽NPY和VIP。在传入肾神经中，表达有部分重叠。 神经肽CGRP和SP以及辣椒素受体TRPV1。另外，我们的初步结果， 首次证实肾传入神经表达感觉神经元的特异性 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神经控制肾功能的理解上的一个关键鸿沟。 我们的中心假设是具有不同神经化学特征的传出和传入神经 通过它们与不同的肾脏结构的关联来区别控制肾功能。我们将使用状态- 最先进的神经生理学和神经解剖学方法，以产生完整的功能和结构 小鼠肾脏的神经控制图。我们还将启动将这些发现翻译到人类肾脏的工作 通过全面的神经解剖学分析。在特定的目标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。在特定的目标2中，我们将测试 假设神经化学上不同的肾神经与大脑中不同的结构有关 肾脏。最后，在具体目标3中，我们将定义肾传出和传入的结构神经生物学。 神经，以及它们与人体肾脏的血管、肾小管和肾盆解剖的关系。

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 Our current understanding is fairly rudimentary and based on classical but outdated methodologies.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.