Functional and molecular identity of renal sensory nerves in hypertension

点击翻译按钮获取中文摘要

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.