Afferent renal nerves, renal inflammation, and hypertension

摘要 高血压(HTN)与交感神经系统活动(SNA)增加和 肾传出神经的活动被认为是重要的。然而，肾脏也受到肾脏的支配。 传入神经，投射到中枢神经系统回路，将SNA调制到各种外周 目标。因此，肾传入神经活动(ARNA)的增加也被认为是导致 SNA与HTN的发病机制。肾去神经(RDNx)治疗人类HTN现在是 有可能。然而，RDNx降低AP的机制仍不清楚。一种新兴的新理论 HTN可能会提供新的见解。据推测，HTN的部分原因是 肾神经、肾炎和HTN。这些发现表明，抗高血压反应 RDNx不是由于对肾功能本身的神经控制的破坏，而是由于阻断了 具有传出和传入肾神经的免疫细胞。 这些发现导致了这一提议的中心假设：DOCA-SALT HTN的部分原因是 促炎细胞因子在肾传入神经上的作用导致神经发生介导性HTN。 四个具体目标将严格检验这一中心假说。具体目标1：调查 细胞因子调节DOCA-SALT大鼠ARNA的神经生理机制。具体目标2： 确定免疫介质对DOCA-SALT大鼠ARNA调节作用的解剖学基础 还有老鼠。具体目标3：相互关联调节降压反应的血流动力学机制 DOCA-SALT HTN的ARNA消融及药理阻断对尿液中肾脏生物标志物的影响 发炎。特定目的4：使用一种新的GCaMP3小鼠体外肾脏切片制剂来鉴定 介导正常和DOCA-SALT小鼠肾传入神经细胞因子调节的分子靶点。 确定免疫细胞与肾传入神经相互作用的机制也将有助于HTN 有助于了解SNA升高的其他肾脏炎症性疾病，如慢性肾功能衰竭。

Abstract Hypertension (HTN) is linked to increased sympathetic nervous system activity (SNA) and increased activity of renal efferent nerves is thought to be important. However, the kidneys are also innervated by renal afferent nerves, which project to central nervous system circuits that modulate SNA to various peripheral targets. As such, increased afferent renal nerve activity (ARNA) is also postulated to contribute to increased SNA and the pathogenesis of HTN. Renal denervation (RDNx) for treatment of HTN in humans is now possible. However, the mechanisms by which RDNx lowers AP remain unknown. An emerging new theory of HTN may provide new insights. It is hypothesized that HTN is caused, in part, by a close relationship between renal nerves, renal inflammation, and HTN. These findings suggest that the antihypertensive response to RDNx is not due to disruption of neural control of renal function per se, but rather, blockade of the interaction of immune cells with efferent and afferent renal nerves. These findings led to the Central Hypothesis of this proposal: DOCA-salt HTN is caused, in part, by the action of proinflammatory cytokines on afferent renal nerves resulting in neurogenically mediated HTN. Four Specific Aims will rigorously test this Central Hypothesis. Specific Aim 1: Investigate the neurophysiological mechanisms by which cytokines modulate ARNA in the DOCA-salt rat. Specific Aim 2: Define the anatomical substrates responsible for modulation of ARNA by immune mediators in DOCA-salt rats and mice. Specific Aim 3: Correlate the hemodynamic mechanisms mediating the anti-hypertensive response to ablation and pharmacological blockade of ARNA in DOCA-salt HTN, to urinary biomarkers of renal inflammation. Specific Aim 4: Employ a novel GCaMP3 mouse ex vivo renal slice preparation to identify molecular targets mediating cytokine modulation of afferent renal nerves in normal and DOCA-salt mice. Identification of the mechanisms by which immune cells interact with renal afferent nerves in HTN will also benefit understanding other renal inflammatory diseases with elevated SNA such as chronic renal failure.