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去肾神经可降低动脉血压 高血压模型。这些降压作用部分归因于 选择性去神经切除肾感觉神经降低动脉血压 血压降至与完全肾去神经相同的程度。尽管我们目前知道 肾神经，严重缺乏解剖、功能和机制方面的知识 负责心血管控制的特定感觉纤维类型。肾感觉神经 检测肾脏中的机械和化学刺激，从而改变钠 重吸收、肾素分泌和交感神经流出。这些反应取决于 对机械和化学敏感的神经纤维尚未明确定义。我们的预赛 使用单细胞转录切割法对肾脏感觉神经元的数据表明存在 两个不同的群体：机械敏感通道Piezo2和化学敏感通道 TRPV1。这一建议的总体假设是，在神经化学上截然不同的人群 表达Piezo2和TRPV1的肾脏感觉神经元介导机械和化学敏感性 肾脏的反应。肾狭窄时这些神经元的神经化学变化 从Piezo2机械敏感纤维的丢失到Piezo2机械敏感纤维的强劲表达和敏感性增加 TRPV1-对交感神经流出和动脉血压升高的化学敏感纤维。目标1 将采用体内单一单位记录，单细胞转录(&gt；40个感觉基因)，以及 光遗传学确定Piezo2和TRPV1表达神经元的程度 对机械和化学敏感的肾脏感觉神经群体。目标2将决定如何 肾狭窄引起的高血压改变了肾脏的机械敏感性和化疗敏感性 传入，感觉神经元的神经化学特征，以及 肾脏。目标3将直接评估Piezo2与TRPV1肾感觉神经纤维的贡献 肾感觉功能和肾血管性高血压的通道。这项提案将界定， 首次报道了肾感觉神经群体的神经化学和功能表型 参与控制动脉血压，解剖定位肾脏的神经支配部位， 并在体内对不同的肾传入纤维种群和通道进行功能测试 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.