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：
8376982
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：
2012
资助国家：
美国
起止时间：
2012-04-01 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，盐的大量消耗导致高血压的发展。这是由于肾脏无法排泄多余的盐。盐敏感性高血压的动物模型异常表现出 Henle环中的NACI吸收增强，包括较厚的上升肢（泰语）。 NACI吸收由泰语主要由Na/k/2ci共转运蛋白NKCC2介导。营地增强了NACI吸收通过刺激NKCC2，而NATIRETICARITATION因子NO通过抑制NKCC2降低了NACI的吸收。在 DAHL盐敏感（SS）大鼠，NO对NACI重吸收的抑制作用减少。在正常动物中，CGMP刺激的磷酸二酯酶2（PDE2）介导了NO的抑制作用通过减少营地，在Thal NACI上重吸收。磷酸二酯酶5（PDE 5）可能反对否通过降解CGMP。目前尚不清楚为什么NO对Thal的NACI重吸收的抑制作用是 Dahl SS大鼠减少。我们假设NO抑制厚的肢体NACI通过激活PDE 2可减少营地。在SS大鼠中，无诱导的NACI抑制作用减少由于PDE 2活性减少。此外，在SS大鼠中增强了PDE 5降解CGMP，进一步钝化 PDE 2激活否。在高盐饮食期间NO的动作减少有助于盐敏感高血压。该假设将以4个目标进行检验。 AIM I.假设：在SS大鼠中，由于营地受损而减少了THAL中NACI的重吸收和腔膜NKCC2 降解。目标II。假设：在SS大鼠中，PDE 2活性降低可降低NACI对NACI的影响重吸收。 AIM III。假设：在SS大鼠中，增强的PDE 5活性降低了CGMP并减少PDE 2 通过NO激活，进一步降低了NO对NACI重吸收的抑制作用。目标IV。假设：在 SS大鼠喂养高盐饮食，PDE 2减少并增强PDE 5活性降低了抑制作用没有NACI的重吸收，导致该菌株的高血压。该项目与中央主题是因为它研究自分泌抗高血压机制中的缺陷如何增强肾脏盐重吸收并导致高血压。该项目的信息将与该信息集成来自所有其他项目。它将使用所有核心。我们的发现将集中于搜索所涉及的基因盐敏感的高血压，可能会导致新疗法用于治疗高血压。