Renal ACE, salt sensitivity and blood pressure control

描述（由申请人提供）：最近的研究强调肾脏炎症在引起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。我们最近发表了肾组织中血管紧张素转换酶（ACE）的活性对于实验性高血压的发展是不可或缺的。具体而言，由于局部（肾脏）Ang II生成受损，缺乏肾ACE的小鼠对传统高血压模型具有抗性。肾angii似乎对几种关键钠转运蛋白的活性至关重要，包括厚升肢Na+/K+/2Cl-转运蛋白（NKCC2）和远小管NaCl共转运蛋白（NCC）；肾脏ACE局部Ang II合成增加导致钠和水潴留和高血压。基于这些发现，本研究将解决以下假设：肾脏ACE/Ang II通路是钠沿肾单位运输的主开关，炎症或其他肾损伤不当激活该开关会触发肾钠失调，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）之后是恢复阶段（1周），最后暴露于高盐饮食（3周）。最初的侮辱(L

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.