Role of the kidneys in hypertension: paracrine actions of NO in the renal medulla

肾脏在高血压中的作用：肾髓质中 NO 的旁分泌作用

• 批准号: 7487606
• 负责人: Maria Marcela Herrera
• 金额: $ 4.86万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487606
• 关键词: AQP1 gene; Blood; Blood Pressure; Blood Vessels; Blood flow; Cell membrane; Chest; Confocal Microscopy; Data; Defect; Development; Diffusion; Electrodes; Endothelium; Fluorescent Dyes; Gene Transfer; Hypertension; Kidney; Knockout Mice; Left; Measures; Mus; Nephrons; Nitric Oxide; Pericytes; Play; Population; Production; Rate; Rectum; Regulation; Relaxation; Renal Blood Flow; Role; Structure of ascending limb of Henle' s loop; Technology; Thick; Thoracic aorta; Time; Tubular formation; Water; basolateral membrane; blood pressure regulation; extracellular; hypertension treatment; kidney medulla; paracrine; tool

DESCRIPTION (provided by applicant): Hypertension afflicts approximately 1/3 of the U.S. population. The kidney plays an important role in the regulation of blood pressure through the regulation of extracellular volume. Renal nitric oxide (NO) plays an important role in the regulation of extracellular volume and thus blood pressure. Inhibition of renal NO production in general and in the renal medulla specifically causes hypertension. The latter is due to changes in medullary blood flow and nephron transport. In the renal medulla, NO dilates the vasa recta pericytes to increase medullary blood flow. At least some of this NO comes from the adjacent thick ascending limb of the loop of Henle (THAL). Free diffusion is assumed to be the primary mechanism whereby NO leaves the THAL and enters the pericyte. However we have recently shown that aquaporin-1 (AQP-1) transports NO across cell membranes 4 times faster than free diffusion and that AQP-1-dependent NO transport is required for endothelium-induced relaxation of thoracic aortas. Although THALs reabsorb no water, their basolateral membranes are water permeable. Our preliminary data show that this is in part due to AQP-1, which is also expressed in the vasa recta. We hypothesize that AQP-1 transports NO out of the THAL and into the vasa recta pericytes. First, we will investigate whether AQP-1 transports NO out of the THAL by measuring NO efflux from single, microperfused THALs isolated from wild-type and AQP-1 knockout (-/-) mice using a NO-selective electrode. Second, we will investigate whether AQP-1 transports NO into vasa recta pericytes by measuring NO influx into single, microperfused vasa recta isolated from wild-type and AQP-1 -/- mice using fluorescent dye and fluorescent confocal microscopy. Third, we will investigate whether AQP-1-dependent NO transport is involved in tubular vascular crosstalk between the THAL and vasa recta pericytes by measuring the effect of stimulating NO production by the THAL on NO influx into descending vasa recta from wild-type and AQP-1 -/- mice using a single, isolated THAL with an adjacent descending vasa recta attached. Finally, we will measure the effect of restoring AQP-1 expression by gene transfer technology specifically in the THAL, vasa recta pericytes, or both on: 1. Efflux of NO out of the THAL, 2. Influx of NO into the Vasa recta and 3) THAL-derived NO-dependent relaxation of vasa recta. Data from this proposal will contribute to our understanding of regulation of renal blood flow. Defects in AQP-1 - dependent NO transport from the THAL to the DVR may play a role in the development of hypertension. Results from this proposal may offer new targets for the development of pharmacological tools for the treatment of hypertension.

描述（由申请人提供）：高血压困扰着大约三分之一的美国人口。肾脏通过调节细胞外体积在调节血压中起着重要作用。肾一氧化氮（NO）在调节细胞外体积和血压中起重要作用。抑制肾NO的产生一般和肾髓质特异性引起高血压。后者是由于髓质血流和肾元运输的改变。在肾髓质，NO扩张直血管周细胞，增加髓质血流量。至少有一部分一氧化氮来自于邻近的Henle环（THAL）的粗升肢。自由扩散被认为是NO离开THAL进入周细胞的主要机制。然而，我们最近的研究表明，水通道蛋白-1 （AQP-1）转运NO的速度比自由扩散快4倍，并且依赖AQP-1的NO转运是内皮诱导的胸主动脉松弛所必需的。虽然THALs不重新吸收水分，但它们的基底外侧膜是透水的。我们的初步数据显示，这部分是由于AQP-1，它也在直肠血管中表达。我们假设AQP-1将NO从THAL转运到血管直血管周细胞。首先，我们将通过使用NO选择电极测量从野生型和AQP-1敲除（-/-）小鼠中分离的单个微灌注THALs的NO外排，来研究AQP-1是否将NO从THAL中运输出去。其次，我们将通过荧光染料和荧光共聚焦显微镜测量野生型和AQP-1 -/-小鼠分离的单个微灌注的直血管内NO的内流，来研究AQP-1是否将NO转运到直血管周细胞。第三，我们将通过测量野生型和AQP-1- /-小鼠单独分离的带有相邻降直血管连接的THAL刺激NO产生对NO流入降直血管的影响，来研究依赖AQP-1的NO运输是否参与了THAL和直血管周细胞之间的管状血管串扰。最后，我们将测量通过基因转移技术恢复AQP-1表达的效果，特别是在THAL、血管直血管周细胞或两者中：从THAL流出的NO， 2。NO流入直肠血管和3)由thal引起的NO依赖性直肠血管松弛。这一建议的数据将有助于我们对肾血流调节的理解。依赖AQP-1的一氧化氮从THAL到DVR的运输缺陷可能在高血压的发展中起作用。这一建议的结果可能为开发治疗高血压的药理工具提供新的靶点。