Collecting duct endothelin-1 and hypertension

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的研究表明，集合管（CD）衍生的内皮素-1 （ET-1）是全身血压和肾钠和水排泄的重要调节因子。基于这项工作，我们假设如下：CD ET-1的产生在需要增加钠和水排泄和降低血压的条件下增加。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PGE2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PGE2抑制CD Na和/或水的再吸收和扩张直血管。由此产生的钠和水排泄在钠负荷或矿物皮质激素过量的情况下限制高血压。CD ET-1可能在血管紧张素II高血压中发挥不同的作用，因为血管紧张素II下调了髓质ET-1系统。该系统在介导抗利尿激素逃逸中也起着至关重要的作用。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。

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.