Salt-sensitive Hypertension and the Thick Ascending Limb

在20%的人口中，高盐摄入量会导致高血压的发生。这是由于 肾脏不能排出过量的盐分。盐敏感型高血压动物模型表现异常 Henle环(包括粗大的泰式升支)对NaCI的吸收增强。氯化钠吸收 主要由Na/K/2CI共转运体NKCC2介导。CAMP促进NaCI吸收 通过刺激NKCC2，而利钠因子NO通过抑制NKCC2而减少对NaCI的吸收。在……里面 在Dahl盐敏感(SS)大鼠中，NO对泰国人重吸收NaCI的抑制作用减弱。 在正常动物中，cGMP刺激的磷酸二酯酶2(PDE2)介导了NO的抑制作用 降低cAMP对Thal-NaCI重吸收的影响。磷酸二酯酶5(PDE 5)可拮抗 不是通过降解cGMP。目前还不清楚为什么NO对Thal重吸收NaCI的抑制作用是 Dahl SS大鼠降低。我们推测，NO通过抑制粗大的上肢NACI重吸收 激活能降低cAMP的PDE-2。在SS大鼠，NO对NaCI重吸收的抑制作用减弱 由于PDE-2活性降低。此外，在SS大鼠中，增强的PDE-5降解cGMP，进一步钝化 NO激活PDE-2。在高盐饮食中NO的作用减少有助于盐敏感 高血压。这一假设将在4个目标中得到检验。目的I.假说：在SS大鼠中，丹参的抑制作用 CAMP受损导致THAL中NO对NaCI重吸收和腔膜NKCC2的影响 退化。目的II.假设：在SS大鼠，PDE-2活性降低降低了NO对NACI的影响 重吸收。目的III.假设：在SS大鼠，PDE-5活性增强可降低cGMP和PDE-2 被NO激活，进一步降低了NO对NaCI重吸收的抑制作用。目标四.假设：在 高盐饲料喂养的SS大鼠，PDE-2活性降低，PDE-5活性增强，抑制作用减弱。 NO对NACI的重吸收，导致了这种菌株的高血压。该项目涉及中环 主题，因为它研究了自分泌抗高血压机制的缺陷如何增强肾盐 重吸收并导致高血压。来自这个项目的信息将与那个整合在一起 从所有其他项目中。它将使用所有内核。我们的发现将把重点放在寻找与 盐敏感型高血压，并可能导致治疗高血压的新疗法。

In 20% of the population, high consumption of salt leads to the development of hypertension. This is due to inability of the kidney to excrete excess salt. Animal models of salt-sensitive hypertension exhibit abnormally enhanced NaCI absorption in the loop of Henle, including the thick ascending limb (THAI). NaCI absorption by the THAI is mediated primarily by the Na/K/2CI cotransporter, NKCC2. cAMP enhances NaCI absorption by stimulating NKCC2, whereas the natriuretic factor NO decreases NaCI absorption by inhibiting NKCC2. In the Dahl salt-sensitive (SS)rat,the inhibitory effect of NO on NaCI reabsorption by the THAI is diminished. In normal animals, the cGMP-stimulated phosphodiesterase 2 (PDE2) mediates the inhibitory effect of NO on THAL NaCI reabsorption by decreasing cAMP. Phosphodiesterase 5 (PDE 5) may oppose the effect of NO by degrading cGMP. It is not clear why the inhibitory effect of NO on NaCI reabsorption by the THAL is decreased in Dahl SS rats. We hypothesize that NO inhibits thick ascending limb NaCI reabsorption by activating PDE 2 which reduces cAMP. In SS rats, NO-induced inhibition of NaCI reabsorption is decreased due to diminished PDE 2 activity. In addition, in SS rats enhanced PDE 5 degrades cGMP, further blunting PDE 2 activation by NO. Reduced action of NO during a high-salt diet contributes to salt-sensitive hypertension. This hypothesis will be tested in 4 aims. Aim I. Hypothesis: In SS rats, the inhibitory effect of NO on NaCI reabsorption and luminal membrane NKCC2 in the THAL is decreased due to impaired cAMP degradation. Aim II. Hypothesis: In SS rats, diminished PDE 2 activity decreases the effect of NO on NaCI reabsorption. Aim III.Hypothesis: In SS rats, enhanced PDE 5 activity lowers cGMP and reduces PDE 2 activation by NO, further decreasing the inhibitory effect of NO on NaCI reabsorption. Aim IV. Hypothesis: In SS rats fed a high-salt diet, diminished PDE 2 and enhanced PDE 5 activity decrease the inhibitory effect of NO on NaCI reabsorption, contributing to the hypertension in this strain. This project relates to the central theme because it studies how a defect in an autocrine anti-hypertensive mechanism enhances renal salt reabsorption and contributes to hypertension. The information from this project will be integrated with that from all other projects. It will use all of the cores. Our findings will focus the search for the genes involved in salt-sensitive hypertension and may lead to new therapies for the treatment of high blood pressure.