Salt-sensitive Hypertension and the Thick Ascending Limb

盐敏感性高血压和上肢粗

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8376982
• 关键词: Animal Model; Animals; Antihypertensive Agents; Consumption; Cyclic AMP; Cyclic GMP; Dahl Hypertensive Rats; Defect; Development; Diet; Enzyme-Linked Immunosorbent Assay; Exhibits; Fluorescence Resonance Energy Transfer; Genes; Henle' s loop; Hormones; Hypertension; Kidney; Lead; Limb structure; Measures; Mediating; Natriuretic Factors; Nephrons; Population; Rattus; Resistance; Role; Sodium Chloride; Soluble Guanylate Cyclase; Testing; Thick; absorption; analog; autocrine; blood pressure regulation; feeding; inhibitor/antagonist; luminal membrane; mRNA Expression; novel; overexpression; phosphodiesterase V; phosphoric diester hydrolase; salt sensitive; saluretic; sodium-potassium chloride cotransporter 2 protein

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，高盐消费导致高血压的发展。这是由于 肾脏不能排出多余的盐分。盐敏感性高血压动物模型表现出异常的 增强的氯化钠吸收的回路的亨利，包括厚升支（泰国）。NaCl吸收 由THAI主要由Na/K/2Cl协同转运蛋白NKCC 2介导。cAMP增强NaCl吸收 通过刺激NKCC 2，而利钠因子NO通过抑制NKCC 2降低NaCl吸收。在 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（PDE 2）介导NO的抑制作用 通过降低cAMP对塔尔NaCl重吸收的影响。磷酸二酯酶5（PDE 5）可对抗 NO通过降解cGMP。目前尚不清楚为什么NO对塔尔重吸收NaCl的抑制作用， 在Dahl SS大鼠中降低。我们假设NO抑制了厚的上升肢体NaCl重吸收， 激活PDE 2，减少cAMP。在SS大鼠中，NO诱导的NaCl重吸收抑制减少， 由于PDE 2活性降低。此外，在SS大鼠中，增强的PDE 5降解cGMP， NO激活PDE 2。在高盐饮食期间，NO的作用降低有助于盐敏感性。 高血压这一假设将在4个目标中进行检验。艾姆岛假设：在SS大鼠中， NO对塔尔中NaCl重吸收和管腔膜NKCC 2的影响由于受损的cAMP而降低 降解Aim II.假设：在SS大鼠中，PDE 2活性降低降低了NO对NaCl的作用。 重吸收目的III.假设：在SS大鼠中，增强PDE 5活性降低cGMP并减少PDE 2 通过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大鼠高盐饮食，减少PDE 2和增强PDE 5活性降低了 NO对NaCl重吸收的抑制作用，导致该品系的高血压。该项目涉及中央 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。该项目的信息将与 所有其他项目。它将使用所有的核心。我们的研究结果将集中在寻找参与 盐敏感性高血压，并可能导致治疗高血压的新疗法。