Collecting duct endothelin-1 and hypertension

CD）-衍生的内皮素-1（ET-1）是全身血压和肾Na+的重要调节剂， 水排泄基于这项工作，我们假设：CD ET-1的产生增加， 第二，Ritieocnesnt设置它在infrgom eonhranlacedoratoNrya，和udilwizziantgercexllc-srepteiocnicative和ddenedutcaergdetinbglo，odinpriceastseure. that activlaleticonning of dCucDt ETB受体和髓质间质细胞ET受体增加髓质一氧化氮和PGE 2 产生，而CD ETA受体的活化增强了减少一氧化氮的超氧化物的形成。 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。所得 钠和水的排泄限制了钠负荷或盐皮质激素过量时的高血压。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下调了髓质 ET-1系统。该系统在介导加压素逃逸中也是至关重要的。总体而言，CD ET-1系统 在正常生理和病理条件下控制血压是必需的。 CD特异性敲除ET-1、ETA受体、ETB受体或ETA和ETB受体的小鼠将 被利用正常生理状态下ET-1对肾功能和血压调节的机制 情况将进行研究。这包括确定CD衍生的ET-1是否在自分泌中起作用， 和/或旁分泌方式，ETA和ETB受体是否对Na和水排泄具有相反的作用 CD源性ET-1是否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机制，以及是否 CD衍生的ET-1引起CD Na和水转运蛋白表达的长期变化。此外，CD- 在盐和/或水保留条件下衍生的ET-1对血压和肾功能的调节将 接受检查。这将包括确定CD衍生的ET-1在控制血压中的作用 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。 这些研究将提供关于CD衍生的ET-1在控制血压中的作用的信息， 正常生理和病理条件下的肾功能。这些信息对于 了解高血压和水盐潴留的肾内机制。

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 IcondRitieocnesnt nsetucedsiesitatinfrgom eonuhranlacebdoratoNrya, anudtiliwziantger cexllc-srepteiocnific angdenredutcaergdetinbglo, odinpdriceastseure.thatActiovlaleticotning ofdCucDt 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.