Renal ACE, salt sensitivity and blood pressure control

肾 ACE、盐敏感性和血压控制

• 批准号: 8918611
• 负责人: Romer Andres Gonzalez-Villalobos
• 金额: $ 21.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8918611
• 关键词: Acute; Address; Affect; Angiotensin II; Biochemical; Blood Pressure; Cell surface; Chronic; Data; Development; Diet; Distal; Epithelial; Epithelial Cells; Excretory function; Exposure to; Financial compensation; Generations; Genetic; Goals; Health; Hypertension; Individual; Inflammation; Inflammatory; Injury; Intake; Kidney; Kidney Diseases; Laboratories; Lead; Limb structure; Modeling; Mus; NG-Nitroarginine Methyl Ester; Nephrons; Pathway interactions; Patients; Peptidyl-Dipeptidase A; Phase; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Process; Protocols documentation; Publishing; Recovery; Regulation; Renal Tissue; Renin-Angiotensin System; Resistance; Role; Sodium; Sodium Chloride; Source; Stress; System; Testing; Thick; Time; Transgenic Model; Tubular formation; Water; Wild Type Mouse; base; blood pressure regulation; in vivo; insight; mouse model; novel; prevent; response; salt intake; salt sensitive hypertension; symporter

DESCRIPTION (provided by applicant): Recent studies emphasize the importance of renal inflammation in causing defective sodium handling by the kidneys, a central feature of salt-sensitive hypertension. Yet, the precise mechanisms by which renal inflammation leads to renal sodium retention are not fully understood. We recently published that the activity of the angiotensin-converting enzyme (ACE) in renal tissues is indispensable for the development of experimental hypertension. Specifically, mice lacking renal ACE are resistant to traditional models of hypertension due to impaired local (renal) Ang II generation. Renal Ang II appears critical to the activity of several key sodium transporters, including the thick ascending limb Na+/K+/2Cl- transporter (NKCC2) and the distal tubule NaCl co- transporter (NCC); increased local Ang II synthesis by renal ACE results in sodium and water retention and hypertension. Based on these findings, this proposal will address the hypothesis that the renal ACE/Ang II pathway is a master switch of sodium transport along the nephron, and inappropriate activation of this switch by inflammation or other renal injury triggers the renal sodium dysregulation that ultimately causes salt- sensitive hypertension. We conducted preliminary studies using the post-L NAME hypertension model. In this, the transient exposure to L-NAME (4 weeks) is followed by a recovery phase (1 week) and finally exposure to a high salt diet (3 weeks). The initial insult (L NAME) induces renal inflammation and leads to salt-sensitivity and hypertension in previously normal (i.e. salt resistant) mice. We now present evidence that mice lacking ACE in renal tissues do NOT develop post L-NAME salt-sensitivity. Further, mice lacking renal ACE maintain a normal renal response to high salt despite substantial levels of renal inflammation induced by the protocol. Two aims are proposed to further investigate these very novel observations: Aim 1 is to determine the quantitative contribution of tubular epithelial ACE to salt-sensitive hypertension. Our hypothesis is that ACE from the epithelial cells of the nephron is the major source of local Ang II in response to the parenchymal inflammation inducing salt-sensitivity. To do this, we created a transgenic model in which tubular ACE expression can be turned on/off; we will investigate the responses of these mice to the post-L NAME model. Aim 2 is to study the in vivo biochemical basis of the renal ACE/Ang II master switch. Our hypothesis is that local Ang II synthesis by renal ACE increases NCC abundance, NKCC2 and NCC phosphorylation (via the kinase SPAK) and cell surface expression of NKCC2 and NCC. To test this, we will determine the regulation of NKCC2 and NCC in wild-type and mice lacking renal ACE during post-L NAME hypertension. By studying this very novel and obligatory interaction between renal injury and the master switch of renal ACE, our studies will provide novel and mechanistic insights into the origins of salt-sensitive hypertension, a condition affecting 1 in every 2 hypertensive patients.

描述（由申请人提供）：最近的研究强调了肾脏炎症在导致肾脏钠处理缺陷中的重要性，这是盐敏感性高血压的中心特征。然而，肾脏炎症导致肾钠潴留的确切机制尚不完全清楚。我们最近发表的研究表明，肾组织中血管紧张素转换酶（ACE）的活性在实验性高血压的发展中是不可或缺的。具体而言，缺乏肾ACE的小鼠由于局部（肾）Ang II生成受损而对传统高血压模型具有抗性。肾血管紧张素II似乎对几种关键钠转运蛋白的活性至关重要，包括粗升支Na+/K+/2Cl-转运蛋白（NKCC 2）和远端小管NaCl协同转运蛋白（NCC）;肾ACE导致的局部血管紧张素II合成增加导致钠和水潴留和高血压。基于这些发现，该提议将解决以下假设：肾ACE/Ang II通路是钠沿着肾单位转运的主开关，并且通过炎症或其他肾损伤不适当地激活该开关触发肾钠失调，其最终导致盐敏感性高血压。我们使用L NAME后高血压模型进行了初步研究。在这种情况下，短暂暴露于L-NAME（4周）之后是恢复期（1周），最后暴露于高盐饮食（3周）。初始侮辱（L NAME）诱导肾脏炎症，并导致先前正常（即耐盐）小鼠的盐敏感性和高血压。我们现在提供的证据表明，肾组织中缺乏ACE的小鼠不会发展后L-NAME盐敏感性。此外，缺乏肾ACE的小鼠维持对高盐的正常肾反应，尽管该方案诱导了显著水平的肾脏炎症。提出了两个目标，以进一步研究这些非常新颖的观察：目的1是确定定量的肾小管上皮ACE盐敏感性高血压的贡献。我们的假设是，ACE从上皮细胞的肾单位是主要来源的本地血管紧张素II在响应实质炎症诱导盐敏感性。为此，我们创建了一个转基因模型，其中管状ACE表达可以打开/关闭;我们将研究这些小鼠对后L NAME模型的反应。目的二是研究肾脏ACE/Ang Ⅱ主开关的体内生化基础。我们的假设是肾ACE的局部Ang II合成增加NCC丰度、NKCC 2和NCC磷酸化（通过激酶SPAK）以及NKCC 2和NCC的细胞表面表达。为了测试这一点，我们将确定在L NAME后高血压期间野生型和缺乏肾ACE的小鼠中NKCC 2和NCC的调节。通过研究肾损伤和肾ACE主开关之间的这种非常新颖和强制性的相互作用，我们的研究将为盐敏感性高血压的起源提供新的机制见解，盐敏感性高血压是每2例高血压患者中就有1例受影响的疾病。