Renal Denervation To Treat Hypertension: Mechanisms and Mediators

项目总结： 高血压(高血压；HTN)在美国仍处于流行水平。虽然HTN病因学 尽管仍有争议，但肾脏仍然是控制血压的关键因素。此外，还提升了 交感神经活动(SNA)和肾脏的神经支配与血压控制密切相关，通过两者 传出(从脑到肾的信号)和传入(肾到脑)神经信号。一大堆实验性的 临床研究表明，切除这些神经，或肾去神经(RDNx)，可以预防和逆转 HTN.尽管这种反HTN反应令人兴奋，但RDNx治疗HTN的机制仍不明确。 目前尚不清楚传出(信号从脑到肾；ERN)和传入(肾到脑；ARN)肾 不同神经群对HTN的作用不同。一般来说，ERN调节肾素的释放，血管阻力， 和钠排泄，而ARNS调节精氨酸加压素(AVP)的分泌和外周SNA。 众所周知，肾神经与肾炎(肾炎)相互作用并影响肾炎，肾炎被认为是导致 HTN.与这些发现一致，我们的实验室最近证明了抗高血压反应 RDNx可能是由于阻断了炎症信号与肾神经之间的相互作用。 具体地说，我们观察到消融所有肾神经(T-RDNx；传出+传入)可减弱HTN并取消HTN 白细胞介素1β、白细胞介素6、单核细胞趋化蛋白-1等炎症细胞因子在DOCA-SALT大鼠模型中的表达 ARN(A-RDNx)只减弱HTN，而不减弱细胞因子。DOCA-盐型HTN和肾炎也是配对的 与正常血压对照组相比，静息肾传入神经活动(ARNA)增加了2.3倍。在……里面 一致，这些数据表明ERN调节炎性贩运，而ARN在这个模型中调节HTN。 根据我们之前的观察和本提案中概述的强有力的初步数据，我们得出了以下结论 可验证性中心假说：(A)肾脏SNA(RSNA)升高促使活化的免疫细胞(例如 T细胞、巨噬细胞)产生促炎细胞因子；(B)这些细胞因子激活或超敏 (C)Arna的增加会反射性地增加外周SNA和AVP的释放，进而导致血压升高。我们 我将通过以下具体目标来检验这一假设：(1)评估慢性肾脏SNA对DOCA-SALT的反应， 以及传入特异性去神经(A-RDNx)的影响。我们将直接测量ARNA和肾脏SNA的变化 与DOCA-SALT大鼠的血压平行。(2)评价肾脏炎症是否改变肾传入神经。 活动性和敏感度。使用建立的体内和一种新的体外方法来敏锐地测量ARNA，我们 将决定肾炎性细胞因子是否会增加静息状态下的ARNA。(3)确定传入肾的作用 神经对DOCA盐的神经体液反应的调节。我们将确定A-RDNx是否会钝化AVP DOCA-SALT HTN模型中的分泌。通过明确肾神经在HTN和肾炎中的特定作用，我们 将从根本上重新定义RDNx临床使用的机制基础，并可能确定治疗方法 HTN治疗的靶点。

PROJECT SUMMARY: High blood pressure (hypertension; HTN) continues at epidemic levels in the United States. Though HTN etiology remains debated, the kidney remains a key contributor to blood pressure control. Moreover, elevated sympathetic nerve activity (SNA) and innervation of the kidney is closely linked to BP control, through both efferent (signal from brain to kidney) and afferent (kidney to brain) nerve signaling. A large body of experimental and clinical studies demonstrates ablation of these nerves, or renal denervation (RDNx), can prevent and reverse HTN. Although this anti-HTN response is exciting, the mechanism by which RDNx treats HTN remains ill-defined. It remains unclear whether efferent (signal from brain to kidney; ERN) and afferent (kidney to brain; ARN) renal nerves populations differentially contribute to HTN. In general, ERNs regulate renin release, vascular resistance, and sodium excretion, whereas ARNs modulates arginine vasopressin (AVP) secretion and peripheral SNA. Renal nerves are known to interact with and influence renal inflammation (nephritis), which is posited to cause HTN. Consistent with these findings, our laboratory has recently demonstrated the antihypertensive response to RDNx may be due to the blockade of the interaction between inflammatory signaling and renal nerves. Specifically, we observed ablation of all renal nerves (T-RDNx; efferent+afferent) attenuated HTN and abolished renal inflammatory cytokines (e.g. IL-1β, IL-6, MCP-1) in the DOCA-salt rat model; however, selective ablation of ARNs (A-RDNx) only attenuated the HTN and not the cytokines. DOCA-salt HTN and nephritis was also paired with a 2.3-fold increase in resting afferent renal nerve activity (ARNA) compared to normotensive controls. In concert, these data suggest ERNs regulate inflammatory trafficking, and ARNs mediate the HTN in this model. With our previous observations and strong preliminary data outlined in this proposal, we formed the following testable Central Hypothesis: (a) Elevated renal SNA (RSNA) drives the infiltration of activated immune cells (e.g. T-cells, macrophage) which produce pro-inflammatory cytokines; (b) These cytokines activate or hypersensitize ARNs; (c) Increased ARNA reflexly raises peripheral SNA and AVP release, and, in turn, blood pressure. We will test this hypothesis with the following specific aims: (1) Asses the chronic renal SNA response to DOCA-salt, and the effect of afferent-specific denervation (A-RDNx). We will directly measure ARNA and renal SNA changes in parallel to blood pressure in the DOCA-salt rat. (2) Evaluate if renal inflammation alters renal afferent nerve activity and sensitivity. Using an established in vivo and a novel ex vivo method to acutely measure ARNA, we will determine if renal inflammatory cytokines increase resting ARNA. (3) Determine the role of afferent renal nerves in the regulation of the neurohumoral response to DOCA-salt. We will determine if A-RDNx blunts AVP secretion in the DOCA-salt HTN model. By defining the specific role of renal nerves in HTN and nephritis, we will fundamentally redefine the mechanistic basis for clinical use of RDNx and potentially identify therapeutic targets for the HTN treatment.