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 血流动力学和血压。不同动物模型和临床试验中的证据 肾神经失神经提示肾感觉神经在慢性肾功能衰竭中起主导作用。 高血压的发病机制和维持。尽管我们目前对肾神经有了解， 严重缺乏对特定关节的解剖学、功能性和机械学知识。 感觉纤维--负责心血管控制的类型。肾感觉神经检测 肾脏内的机械和化学刺激，从而改变钠的重吸收， 肾素分泌和交感神经流出。这些反应依赖于机械和 尚未明确定义的化学敏感神经纤维。我的初步数据使用 肾感觉神经元的单细胞聚合酶链式反应显示存在两种截然不同的 种群：Piezo2和TRPV1。基于这些数据，我假设Piezo2和TRPV1 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、血流动力学和血压。这项提案的总体目标是 神经化学图谱Piezo2和TRPV1表达感觉神经和评估机械 肾脏中的化学感觉会导致高血压。具体地说，我将：1) 使用单单位录音和单细胞转录切割法来检查 Piezo2和TRPV1表达的神经元代表对机械和化学敏感的肾脏 感觉神经群，2)使用光遗传学和转基因小鼠来确定Piezo2和 TRPV1纤维介导肾脏对机械和化学敏感刺激的感觉反应 改变SNA和BP，以及3)评估Piezo2和TRPV1感觉的急性和慢性贡献 纤维在维持肾血管性高血压中的作用。这项工作将定义肾脏投射 参与血压肾反射控制的传入神经群，解剖图谱 在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有病理作用的活体。

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.