Functional and molecular identity of renal sensory nerves in hypertension

摘要 肾传出和传入感觉神经协调肾功能，中枢 血液动力学和血压。各种动物模型和临床试验的证据表明， 肾神经去神经支配表明肾感觉神经在肾功能衰竭中的主要作用。 高血压的发病机制和维持。尽管我们目前对肾神经的了解， 严重缺乏关于特定的解剖学，功能和机械知识， 负责心血管控制的感觉纤维类型。肾感觉神经检测 肾脏内的机械和化学刺激并因此改变钠重吸收， 肾素分泌和交感神经流出。这些反应依赖于机械和 化学敏感性神经纤维尚未明确定义。我的初步数据使用 对肾感觉神经元的单细胞PCR显示存在两种不同的 Piezo 2和TRPV 1。基于这些数据，我假设Piezo 2和TRPV 1 表达肾感觉神经分别检测机械和化学敏感刺激， 并影响肾功能、血液动力学和血压。本提案的总体目标是 神经化学分析Piezo 2和TRPV 1表达的感觉神经，并评估机械- 和化学感受，导致高血压。具体来说，我将：1） 使用单单位记录和单细胞转录组学来检查 Piezo 2和TRPV 1表达神经元代表机械和化学敏感性肾 感觉神经群体，2）使用光遗传学和转基因小鼠来确定Piezo 2和 TRPV 1纤维介导对机械和化学敏感刺激的肾感觉反应， 改变SNA和BP，以及3）评估Piezo 2和TRPV 1感觉神经元的急性和慢性贡献。 纤维在维持肾血管性高血压中的作用。这项工作将定义肾投射 参与血压肾反射控制的传入感觉神经群，解剖图 肾脏中的神经支配部位，并在功能上测试不同的肾脏传入纤维群， 在高血压和心血管疾病中具有病理作用。

ABSTRACT Renal efferent and afferent sensory nerves coordinate renal function, central hemodynamics, and blood pressure. Evidence in diverse animal models and clinical trials of renal nerve denervation have suggested a predominant role of renal sensory nerves in the pathogenesis and maintenance of hypertension. 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. My preliminary data using single-cell PCR on renal sensory neurons demonstrates the existence of two distinct populations: Piezo2 and TRPV1. Based on these data, I hypothesize Piezo2 and TRPV1 expressing renal sensory nerves detect mechano- and chemo-sensitive stimuli, respectively, and influence renal function, hemodynamics, and BP. The overall goal of this proposal is to neurochemically profile Piezo2 and TRPV1 expressing sensory nerves and assess mechano- and chemo-sensation in the kidney that contributes to hypertension. Specifically, I will: 1) employ single-unit recordings and single-cell transcriptomics to examine the extent by which Piezo2 and TRPV1-expressing neurons represent mechano- and chemo- sensitive renal sensory nerve populations, 2) use optogenetics and transgenic mice to determine if Piezo2 and TRPV1 fibers mediate renal sensory responses to mechano- and chemo-sensitive stimuli and alter SNA and BP, and 3) assess acute and chronic contributions of Piezo2 and TRPV1 sensory fibers in the maintenance of renovascular hypertension. This work will define renal-projecting afferent sensory nerve populations involved in renal-reflex control of BP, anatomically map innervation sites in the kidney, and functionally test distinct renal afferent fiber populations in vivo that have a pathological role in hypertension and cardiovascular disease.