The absence of intrarenal ACE protects against hypertension
The absence of intrarenal ACE protects against hypertension
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DOI：
10.1172/jci65460
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发表时间：
2013-05-01
影响因子：
15.9
通讯作者：
McDonough, Alicia A.
中科院分区：
文献类型：
--
作者：
Gonzalez-Villalobos, Romer A.;Janjoulia, Tea;McDonough, Alicia A.
肾内肾素-血管紧张素系统(RAS)的激活可独立于全身RAS而诱发高血压。然而，肾内血管紧张素II升高血压的确切机制从未被确定。为此，我们研究了缺乏肾脏血管紧张素转换酶(ACE)的小鼠对实验性高血压的反应。在这里，我们发现肾血管紧张素转换酶的缺失显著地抑制了血管紧张素转换酶II输注(一种高血清血管紧张素转换酶II的模型)或一氧化氮合成抑制(一种低血清血管紧张素转换酶II的模型)引起的高血压。此外，野生型小鼠对高血清Ang II的肾脏反应，包括肾内Ang II蓄积、钠和水保留、Henle环(NKCC2)和远端肾单位(NCC、ENaC和Pendrin)离子转运体以及转运体激活激酶Spak和OSR1的激活，在缺乏肾脏ACE的小鼠中得到有效预防。这些发现表明，ACE代谢在肾脏对高血压刺激的反应中起着基础性作用。特别是，肾脏ACE活性需要增加局部Ang II，刺激Henle环和远端肾单位的钠转运，并诱导高血压。
Activation of the intrarenal renin-angiotensin system (RAS) can elicit hypertension independently from the systemic RAS. However, the precise mechanisms by which intrarenal Ang II increases blood pressure have never been identified. To this end, we studied the responses of mice specifically lacking kidney angiotensin-converting enzyme (ACE) to experimental hypertension. Here, we show that the absence of kidney ACE substantially blunts the hypertension induced by Ang II infusion (a model of high serum Ang II) or by nitric oxide synthesis inhibition (a model of low serum Ang II). Moreover, the renal responses to high serum Ang II observed in wild-type mice, including intrarenal Ang II accumulation, sodium and water retention, and activation of ion transporters in the loop of Henle (NKCC2) and distal nephron (NCC, ENaC, and pendrin) as well as the transporter activating kinases SPAK and OSR1, were effectively prevented in mice that lack kidney ACE. These findings demonstrate that ACE metabolism plays a fundamental role in the responses of the kidney to hypertensive stimuli. In particular, renal ACE activity is required to increase local Ang II, to stimulate sodium transport in loop of Henle and the distal nephron, and to induce hypertension.