Collecting duct endothelin-1 and hypertension

描述（由申请人提供）：我们实验室最近的研究，利用细胞特异性基因靶向，表明集合管（CD）衍生的内皮素-1（ET-1）是全身血压和肾脏Na和水排泄的重要调节剂。基于这项工作，我们假设如下：CD ET-1的生产增加的条件下，需要增强钠和水的排泄和降低血压。CD ETB受体和髓质间质细胞ET受体的激活增加了髓质一氧化氮和PGE 2的产生，而CD ETA受体的激活增强了超氧化物的形成，从而减少了一氧化氮。一氧化氮和前列腺素E2抑制CD Na和/或水重吸收和扩张髓质直血管。在钠负荷或盐皮质激素过量的情况下，由此产生的钠和水排泄限制了高血压。CD ET-1可能在血管紧张素II高血压中发挥不同的作用，这是由于血管紧张素II下调髓质ET-1系统。该系统在介导加压素逃逸中也是至关重要的。总的来说，CD ET-1系统在正常生理和病理条件下控制血压是必不可少的。 将使用CD特异性敲除ET-1、ETA受体、ETB受体或ETA和ETB受体的小鼠。本文将探讨正常生理条件下ET-1对肾功能和血压调节的机制。这包括确定CD衍生的ET-1是否以自分泌和/或旁分泌方式起作用，ETA和ETB受体是否对Na和水排泄以及血压具有相反的作用，CD衍生的ET-1是否以及如何调节髓质血流，CD衍生的ET-1与一氧化氮、PGE 2和超氧化物系统相互作用的意义和机制，以及CD衍生的ET-1是否引起CD Na和水转运蛋白表达的长期变化。此外，将检查盐和/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DOCA/盐高血压、血管紧张素II高血压和AVP过量中控制血压和/或维持肾功能的作用。 这些研究将提供有关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的作用的信息。这些信息对于理解高血压、盐和水潴留的肾内机制非常重要。

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.