Substitution of connexin40 with connexin45 prevents hyperreninemia and attenuates hypertension
Substitution of connexin40 with connexin45 prevents hyperreninemia and attenuates hypertension
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DOI：
10.1038/ki.2008.637
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发表时间：
2009-03-01
影响因子：
19.6
通讯作者：
Wagner, Charlotte
中科院分区：
文献类型：
--
作者：
Schweda, Frank;Kurtz, Lisa;Wagner, Charlotte
连接蛋白（Cxs）是一个跨膜蛋白家族，形成具有独特和冗余生物物理功能的间隙连接。肾小球旁细胞表达Cx40，它对控制血压和血管紧张素II分泌肾素至关重要，缺乏Cx40的小鼠血浆肾素高，高血压。为了检查正常肾小球旁细胞功能是否依赖于Cx40的独特特性，我们使用敲入法测量了Cx40编码序列被Cx45编码序列取代的小鼠肾素释放。我们首先发现敲入策略确实导致了这些小鼠肾小球旁细胞中Cx45的表达，而不是Cx40的表达。敲入小鼠血浆肾素浓度与野生型小鼠相近。当Cx45被敲入基因座时，Cx40基因敲除小鼠的高血压显著降低，但与野生型小鼠相比仍保持轻度升高。依那普利阻断血管紧张素II的形成可以增加野生型和Cx45敲除小鼠的血浆肾素浓度，而Cx40敲除小鼠则没有。将血管紧张素II输注到离体灌注的肾脏中导致肾素释放减少，这一现象在Cx40基因敲除小鼠中有所减弱。然而，在Cx45敲入小鼠中，血管紧张素II抑制肾素释放的效果与野生型小鼠相似。单侧肾动脉狭窄增加了野生型和Cx45敲除小鼠的血浆肾素浓度和血压，但在Cx40敲除小鼠中没有。由于Cx40可以被Cx45取代，而Cx45是一种电导率明显较低的连接蛋白，因此我们认为肾素释放的调节并不依赖于这些通道蛋白的独特电性能。
Connexins (Cxs) are a family of transmembrane proteins that form gap junctions with unique and redundant biophysical functions. Juxtaglomerular cells express Cx40, which is crucial to the control of renin secretion by blood pressure and angiotensin II, and mice that lack Cx40 have high plasma renin and hypertension. To examine whether normal juxtaglomerular cell function depends on the unique properties of Cx40, we measured renin release in mice where the coding sequence for Cx40 was replaced by that for Cx45, using the knock-in method. We first found that the knock-in strategy indeed resulted in expression of Cx45 but not Cx40 in the juxtaglomerular cells of these mice. The plasma renin concentration of the knock-in mice was similar to that in wild-type mice. The high blood pressure of the Cx40 knockout mice was significantly reduced when Cx45 was knocked into the locus but remained mildly elevated compared to wild-type mice. Blockade of angiotensin II formation by enalapril increased the plasma renin concentration in wild-type and the Cx45 knock-in mice but not in the Cx40 knockout mice. Infusion of angiotensin II into isolated perfused kidneys results in decreased renin release, a phenomenon that was attenuated in the Cx40 knockout mice. However, in the Cx45 knock-in mice, angiotensin II suppressed renin release similar to its effect in wild type mice. Unilateral renal artery stenosis increased the plasma renin concentration and blood pressure in both the wild-type and the Cx45 knock-in mice but not in the Cx40 knockout mice. Since Cx40 can be replaced by Cx45, a connexin with a significantly lower conductivity, we suggest that the regulation of renin release is not dependent on the unique electrical properties of these channel proteins.