Collecting duct endothelin-1 and hypertension

集合管内皮素-1 与高血压

• 批准号: 6849014
• 负责人: Donald E Kohan
• 金额: $ 36.4万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849014
• 关键词: angiotensin /renin /aldosterone hypertension; autocrine; blood pressure; electrolyte balance; endothelin; gene expression; genetically modified animals; hormone receptor; hormone regulation /control mechanism; hypertension; kidney circulation; kidney function; laboratory mouse; nitric oxide; nitric oxide synthase; paracrine; prostaglandin E; protein isoforms; protein structure function; saluresis; sodium channel; superoxides; vasopressins; water channel

DESCRIPTION (provided by applicant): Recent studies from our laboratory, utilizing cell-specific gene targeting, indicate that collecting duct (CD)-derived endothelin-1 (ET-1) is an important regulator of systemic blood pressure and renal Na and water excretion. Based on this work, we hypothesize the following: CD ET-1 production is increased in conditions necessitating enhanced Na and water excretion and reduced blood pressure. Activation of CD ETB receptors and medullary interstitial cell ET receptors increases medullary nitric oxide and PGE2 production, while activation of CD ETA receptors enhances superoxide formation which reduces nitric oxide. Nitric oxide and PGE2 inhibit CD Na and/or water reabsorption and dilate medullary vasa recta. The resultant Na and water excretion limits hypertension in the setting of Na loading or mineralocorticoid excess. CD ET-1 may play a different role in angiotensin II hypertension due to angiotensin II down-regulation of the medullary ET-1 system. This system is also crucial in mediating vasopressin escape. Overall, the CD ET-1 system is essential in controlling blood pressure under normal physiologic as well as pathologic conditions. Mice with CD-specific knockout of ET-1, ETA receptor, ETB receptor, or both ETA and ETB receptors will be used. The mechanisms of ET-1 regulation of renal function and blood pressure under normal physiologic circumstances will be studied. This includes determination of whether CD-derived ET-1 acts in an autocrine and/or paracrine fashion, whether ETA and ETB receptors have opposing effects on Na and water excretion and blood pressure, whether and how CD-derived ET-1 regulates medullary blood flow, significance and mechanisms of CD-derived ET-1 interaction with nitric oxide, PGE2 and superoxide systems, and whether CD-derived ET-1 causes long-term changes in CD Na and water transporter expression. In addition, CD-derived ET-1 regulation of blood pressure and renal function under salt and/or water retaining conditions will be examined. This will include determination of the role of CD-derived ET-1 in controlling blood pressure and/or maintaining renal function in DOCA/salt hypertension, angiotensin II hypertension, and AVP excess. These studies will provide information on the role of CD-derived ET-1 in controlled blood pressure and renal function under normal physiologic as well as pathologic conditions. Such information is important in understanding intrarenal mechanisms responsible for hypertension and salt and water retention.

描述（由申请人提供）：我们实验室最近利用细胞特异性基因靶向进行的研究表明，集合管（CD）衍生的内皮素-1（ET-1）是全身血压以及肾钠和水的重要调节剂排泄。基于这项工作，我们做出以下假设：在需要增强钠和水排泄以及降低血压的条件下，CD ET-1 的产生会增加。 CD ETB 受体和髓质间质细胞 ET 受体的激活会增加髓质一氧化氮和 PGE2 的产生，而 CD ETA 受体的激活会增强超氧化物的形成，从而减少一氧化氮。一氧化氮和 PGE2 抑制 CD Na 和/或水的重吸收并扩张髓质直肠。由此产生的钠和水排泄可限制钠负荷或盐皮质激素过量的情况下的高血压。由于血管紧张素II下调髓质ET-1系统，CD ET-1可能在血管紧张素II高血压中发挥不同的作用。该系统对于介导加压素逃逸也至关重要。总体而言，CD ET-1 系统对于正常生理和病理条件下控制血压至关重要。 将使用具有 ET-1、ETA 受体、ETB 受体或 ETA 和 ETB 受体的 CD 特异性敲除的小鼠。研究正常生理情况下ET-1调节肾功能和血压的机制。这包括确定 CD 衍生的 ET-1 是否以自分泌和/或旁分泌方式发挥作用，ETA 和 ETB 受体是否对钠和水排泄和血压有相反的作用，CD 衍生的 ET-1 是否以及如何调节髓血CD 衍生的 ET-1 与一氧化氮、PGE2 和超氧化物系统相互作用的流程、意义和机制，以及 CD 衍生的 ET-1 是否会导致 CD Na 和水转运蛋白表达的长期变化。此外，还将检查在盐和/或水保留条件下CD衍生的ET-1对血压和肾功能的调节。这将包括确定 CD 衍生的 ET-1 在控制血压和/或维持 DOCA/盐高血压、血管紧张素 II 高血压和 AVP 过量的肾功能中的作用。 这些研究将提供关于 CD 衍生的 ET-1 在正常生理和病理条件下控制血压和肾功能中的作用的信息。这些信息对于理解导致高血压和盐和水潴留的肾内机制很重要。