Identification of mechano versus chemo-sensitive renal sensory neurons in hypertension

摘要 在多项临床试验和实验动物中，肾脏去神经支配降低动脉血压 高血压模型。这些抗高血压作用部分归因于 去除肾感觉神经，因为肾感觉神经的选择性去神经支配降低了动脉 血压与完全肾去神经相同。尽管我们现在知道 肾神经，严重缺乏解剖，功能和机械知识， 负责心血管控制的特定感觉纤维类型。肾感觉神经 检测肾脏内的机械和化学刺激， 重吸收、肾素分泌和交感神经流出。这些反应取决于 机械和化学敏感的神经纤维，尚未明确定义。我们的初步 对肾感觉神经元使用单细胞转录组学的数据表明， 两个不同的群体：机械敏感通道Piezo 2和化学敏感通道 TRPV 1。这一提议的总体假设是，神经化学上不同的群体， 表达Piezo 2和TRPV 1的肾感觉神经元介导机械和化学敏感性 肾脏的反应。这些神经元在肾狭窄中开关的神经化学特征 从Piezo 2-mechanosensitive纤维的损失到强大的表达和增加的敏感性， TRPV 1-化学敏感纤维交感神经流出和动脉血压升高。要求1 将采用体内单单位记录，单细胞转录组学（>40个感觉基因）， 光遗传学，以确定Piezo 2和TRPV 1表达神经元代表 机械和化学敏感的肾感觉神经群。目标2将决定如何 肾狭窄引起的高血压改变了肾组织的机械敏感性和化学敏感性 传入，感觉神经元的神经化学特征，以及 肾目的3将直接评估Piezo 2与TRPV 1肾感觉纤维的贡献 以及通向肾感觉功能和肾血管性高血压的通道。该提案将界定， 这是第一次，肾感觉神经群的神经化学和功能表型 参与动脉血压的控制，解剖学上绘制肾脏中的神经支配部位， 并在功能上测试体内不同的肾传入纤维群和通道， 高血压的病理作用。

ABSTRACT Renal denervation lowers arterial blood pressure in multiple clinical trials and experimental animal models of hypertension. These anti-hypertensive effects have been partly attributed to the removal of renal sensory nerves as selective denervation of renal sensory nerves lowers arterial blood pressure to the same extent as total renal denervation. Despite our current knowledge of renal nerves, there is a severe lack of anatomical, functional, and mechanistic knowledge about the specific sensory fiber-types responsible for cardiovascular control. Renal sensory nerves detect mechanical and chemical stimuli within the kidneys and consequently alter sodium reabsorption, renin secretion, and sympathetic outflow. These responses are dependent on mechano- and chemo- sensitive nerve fibers which have not been clearly defined. Our preliminary data using single-cell transcriptomics on renal sensory neurons demonstrates the existence of two distinct populations: the mechanosensitive channel Piezo2 and chemosensitive channel TRPV1. The overall hypothesis of this proposal is that neurochemically distinct populations of renal sensory neurons expressing Piezo2 and TRPV1 mediate mechano- and chemo-sensitive responses in the kidney. The neurochemical profile of these neurons switches in renal stenosis from a loss of Piezo2-mechanosensitive fibers to robust expression and increased sensitivity of TRPV1-chemosensitive fibers to elevated sympathetic outflow and arterial blood pressure. Aim 1 will employ in vivo single-unit recordings, single-cell transcriptomics (>40 sensory genes), and optogenetics to determine the extent by which Piezo2 and TRPV1-expressing neurons represent mechano- and chemo- sensitive renal sensory nerve populations. Aim 2 will determine how hypertension produced by renal stenosis alters the mechano- versus chemosensitivity of renal afferents, the neurochemical profile of sensory neurons, and the sensory innervation of the kidney. Aim 3 will directly assess the contribution of Piezo2 versus TRPV1 renal sensory fibers and channels to renal sensory function and renovascular hypertension. This proposal will define, for the first time, the neurochemical and functional phenotype of renal sensory nerve populations involved in the control of arterial blood pressure, anatomically map innervation sites in the kidney, and functionally test distinct renal afferent fibers populations and channels in vivo that have a pathological role of hypertension.