Salt-sensitive Hypertension and the Thick Ascending Limb

盐敏感性高血压和上肢粗

基本信息

批准号：
7595339
负责人：
Pablo A. Ortiz
金额：
$ 31.11万
依托单位：
HENRY FORD HEALTH SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

项目摘要

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.

在20%的人口中，高盐摄入会导致高血压的发生。这是由于肾脏无法排出多余的盐分。盐敏感性高血压动物模型表现异常增强亨利袢（包括粗升肢（THAI））中的 NaCl 吸收。氯化钠吸收 THAI 主要由 Na/K/2CI 协同转运蛋白 NKCC2 介导。 cAMP 增强 NaCl 吸收通过刺激 NKCC2，而利尿钠因子 NO 通过抑制 NKCC2 来减少 NaCl 吸收。在 Dahl盐敏感(SS)大鼠中,NO对THAI重吸收NaCl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 NO 的抑制作用通过减少 cAMP 来影响 THAL NaCl 重吸收。磷酸二酯酶 5 (PDE 5) 可能会对抗通过降解 cGMP 产生 NO。目前还不清楚为什么 NO 对 THAL 的 NaCl 重吸收有抑制作用。 Dahl SS 大鼠中减少。我们假设 NO 通过抑制厚升肢 NaCl 重吸收激活 PDE 2，减少 cAMP。在 SS 大鼠中，NO 诱导的 NaCl 重吸收抑制减弱由于 PDE 2 活性降低。此外，在 SS 大鼠中，增强的 PDE 5 会降解 cGMP，进一步减弱 NO 激活 PDE 2。高盐饮食期间一氧化氮的作用减少导致盐敏感高血压。该假设将在 4 个目标中进行检验。目的 I. 假设：在 SS 大鼠中，氯化钠重吸收和管腔膜上的 NO 由于 cAMP 受损，THAL 中的 NKCC2 减少降解。目标二。假设：在 SS 大鼠中，PDE 2 活性降低会降低 NO 对 NaCl 的影响重吸收。目标 III.假设：在 SS 大鼠中，PDE 5 活性增强会降低 cGMP 并减少 PDE 2 被NO激活，进一步降低NO对NaCl重吸收的抑制作用。目标四。假设：在 SS大鼠饲喂高盐饮食，PDE 2 减少和PDE 5 活性增强，降低了抑制作用 NO 影响 NaCl 重吸收，导致该菌株出现高血压。本项目涉及中央主题，因为它研究自分泌抗高血压机制的缺陷如何增加肾盐重吸收并导致高血压。该项目的信息将与该项目集成来自所有其他项目。它将使用所有核心。我们的研究结果将集中于寻找参与的基因盐敏感性高血压可能会导致治疗高血压的新疗法。