Nerohumoral and Renal Mechanisms of Hypertension

神经体液系统和肾脏在心血管动力学的长期控制中密切相关。我们的 以前的研究提供了证据，以压力受损为表现的肾功能异常 到目前为止，在所有形式的慢性高血压研究中，钠尿起着关键作用。一些反常现象 压力性钠尿起源于肾内，但许多是通过激活神经体液机制而发生的 损害肾脏排泄能力。出于这个原因，我们的研究计划的主要部分已经被 了解调节肾功能的神经体液和肾内机制以及如何 这些在慢性高血压中会发生改变。我们最近的工作集中在肥胖的机制上 高血压与人类原发性高血压有特殊的相关性。我们提供的证据表明 肾交感神经活动(RSNA)的激活在肥胖性高血压的病理生理过程中起重要作用。 我们还发现，瘦素，一种从脂肪细胞释放的细胞因子，有助于交感 神经系统(SNS)激活和血压升高(BP)主要通过刺激中枢神经来实现 系统(CMS)前阿片黑素皮质素(POMC)途径。然而，CMS电路和细胞信号 瘦素-黑素皮质素系统对RSNA、BP和新陈代谢的慢性影响机制 人们对此了解甚少。这一建议的中心假设是瘦素-黑素皮质素激活在不同的 和通过多个细胞内信号通路可以不同地和独立地 调节食欲、氧耗(VOZ)、能量消耗、RSNA和BP。具体目标1将 确定瘦素受体在前脑、前额叶和室旁(PVN)神经元构成中的作用 瘦素对代谢和心血管功能的调节及对瘦素慢性作用的调节 食欲、V02和能量消耗、RSNA和BP。具体目标2将确定 前脑、POMC和PVN神经元中STAT3、Shp2-MAPK和lrs2-PI3K信号在结构调控中的作用 代谢和心血管功能以及在调节慢性食欲抑制、VO2和能量方面的作用 瘦素的支出、RSNA和血压作用。特异性靶点3将确定黑素皮质素4受体的作用 前脑和下丘脑室旁核神经元(MC4R)的激活在控制代谢和心血管功能中的作用，以及 在调节慢性食欲抑制、VO2和能量消耗、RSNA和BP等方面发挥瘦素的作用。 这些研究将使用新的小鼠模型，在该模型中，瘦素受体或三个主要的瘦素信号通路 (STATS、lrs2-PI3K和Shp2-MAPK)在前脑、POMC或PVN中被Cre/loxP重组酶删除 神经元或整个大脑来确定大脑区域和细胞信号机制，这些机制介导 瘦素的慢性作用，以及构成控制体重、身体总摄氧量和能量消耗的因素， 血糖稳态、RSNA和BP。中枢神经系统特定区域MC4R的激活在介导中枢神经系统损伤中的作用 瘦素的慢性作用将在MC4R突变的小鼠(loxTB-MC4R“‘’小鼠)中确定，其中MC4R 在前脑、POMC或PVN神经元，或整个大脑中被“拯救”。综合生理学方法， 包括24小时全天监测BP、RSNA、肾功能和代谢功能，并结合 独特的遗传模型为阐明复杂的中枢神经系统通路和 瘦素-黑素皮质素系统差异性调节BP、交感神经活动的信号通路 以及决定能量平衡的代谢功能。

The neurohumoral systems and kidneys are closely linked in long-term control of cardiovascular dynamics. Our previous studies provided evidence that abnormal kidney function, manifested by impaired pressure natriuresis, plays a key role in all forms of chronic hypertension studied thus far. Some abnormalities of pressure natriuresis originate intrarenally, but many occur through activation of neurohumoral mechanisms that impair renal excretory capability. For this reason, a major part of our research program has been directed toward understanding the neurohumoral and intrarenal mechanisms that regulate kidney function and how these are altered in chronic hypertension. Our recent work has focused on the mechanisms of obesity hypertension which has special relevance to human essential hypertension. We provided evidence that activation of renal sympathetic nerve activity (RSNA) plays a major role in the pathophysiology of obesityhypertension. We also found that leptin, a cytokine released from adipocytes, contributes to sympathetic nervous system (SNS) activation and increased blood pressure (BP) mainly by stimulating the central nervous system (CMS) pro-opiomelanocortin (POMC) pathway. However, the CMS circuits and cell signaling mechanisms that mediate the chronic effects of the leptin-melanocortin system on RSNA, BP, and metabolism are poorly understood. The central hypothesis of this proposal is that leptin-melanocortin activation in distinct areas of the brain and through multiple intracellular signaling pathways can differentially and independently regulate appetite, oxygen consumption (VOz) and energy expenditure, RSNA and BP. Specific Aim 1 will determine the role of leptin receptors in the forebrain, POMC and paraventricular (PVN) neurons in constitutive regulation of metabolic and cardiovascular functions and in mediating the chronic actions of leptin on control of appetite, V02 and energy expenditure, RSNA, and BP. Specific Aim 2 will determine the specific roles of Stat3, Shp2-MAPK, and lrs2-PI3K signaling in the forebrain, POMC and PVN neurons in constitutive regulation of metabolic and cardiovascular functions and in mediating the chronic appetite suppression, VO2 and energy expenditure, RSNA, and BP actions of leptin. Specific Aim 3 will determine the role of melanocortin 4 receptor (MC4R) activation in the forebrain and PVN neurons in controlling metabolic and cardiovascular functions, and in mediating the chronic appetite suppression, VO2 and energy expenditure, RSNA, and BP actions of leptin. These studies will use novel mouse models in which the leptin receptor or the 3 main leptin signaling pathways (StatS, lrs2-PI3K, and Shp2-MAPK) are deleted by Cre/loxP recombinase in the forebrain, POMC or PVN neurons or in the entire brain to determine the brain regions and cell signaling mechanisms that mediate the chronic actions of leptin, and that constitutively control body weight, total body VO2 and energy expenditure, glucose homeostasis, RSNA and BP. The role of MC4R activation in specific CNS regions in mediating the chronic actions of leptin will be determined in mice with mutated MC4R (loxTB-MC4R"'' mice) where the MC4R is "rescued" in the forebrain, POMC or PVN neurons, or the entire brain. Integrative physiological methods, including 24 hr/day monitoring of BP, RSNA, kidney function, and metabolic functions, in combination with unique genetic models provide a novel and powerful approach to elucidate the complex CNS circuits and signaling pathways by which the leptin-melanocortin system differentially regulates BP, sympathetic activity and metabolic functions that determine energy balance.