Response to Role of Epithelial Sodium Channels in the Renal Myogenic Response?
Response to Role of Epithelial Sodium Channels in the Renal Myogenic Response?
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对上皮钠通道在肾生肌反应中作用的反应？
DOI：
10.1161/hypertensionaha.109.147454
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Drummond,Heather
中科院分区：
文献类型：
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作者：
Drummond,Heather
Loutzenhiser 和 Aaronson1 认为，1 mol/L 的阿米洛利和苯扎米尔缺乏作用表明，传入小动脉中“[上皮钠通道] ENaC 在生肌信号传导中几乎没有发挥任何作用”。他们是正确的。然而，我们并不假设经典的“ENaC 通道”（由 ENaC 形成）充当血管机械传感器。 1 我们假设上皮细胞中形成 ENaC 通道的蛋白质（即 ENaC 和 ENaC）与相关的酸敏感离子通道 (ASIC) 蛋白质结合形成机械传感器，2 这是一个非常重要的区别。我们使用秀丽隐杆线虫机械传感器作为哺乳动物血管机械传感器的模型，因为 ENaC 蛋白与形成秀丽隐杆线虫机械传感器孔的蛋白质相关。在此模型中，机械传感器由离子通道 (ENaC-ASIC) 形成，离子通道通过与细胞外基质和细胞骨架蛋白的相互作用进行束缚和门控。 3 由于缺乏沉默血管退化蛋白的方法，广谱 ENaC-ASIC 抑制剂（例如阿米洛利）最初被用来确定 ENaC 蛋白作为生肌反应介质的重要性。由于预测的机械传感器的异聚性质以及电化学梯度、蛋白质修饰和剪接变体对阿米洛利敏感性的潜在影响，我们并不期望肌源反应的阿米洛利敏感性与表达系统和天然上皮细胞中 ENaC 蛋白形成的通道的敏感性精确匹配。 4, 5 因此，阿米洛利特异性存在差异是预料之中的，因为血管机械传感器不是经典的 ENaC 通道。 Loutzenhiser 和 Aaronson1 还表明，“直接电生理学方法可能最终解决这个问题，并确定是否在传入小动脉肌细胞中观察到具有 ENaC 功能和药理学特性的通道。”虽然通过电生理学在血管平滑肌细胞中找到ENaC通道会很方便，但未能找到这样的通道并不一定意味着ENaC蛋白在血管平滑肌细胞中不起作用。线虫文献表明野生型简并蛋白机械传感器模型是电沉默的。 3 因此，含有 ENaC 的机械传感器可能是电静音的。那么问题就变成了通道是否被门控。如果细胞外基质对于门控机械传感器至关重要，正如模型预测的那样，那么通过酶解来准备血管平滑肌细胞以进行电生理评估会破坏门控所必需的细胞外基质。因此，电沉默通道和无门控机制可以很容易地解释 ENaC 通道电生理学证据的缺失。ENaC 蛋白功能的证据可能需要使用转基因动物。确定 ENaC 和 ASIC 蛋白对转基因动物生肌反应的重要性的研究正在进行中。最近的研究表明，ENaC 水平降低的小鼠改变了肌源反应性和血流自动调节。 6 尽管这些研究表明 ENaC/ASIC 蛋白在介导肌源性收缩中发挥作用，但仍需要更多研究来了解 ENaC/ASIC 蛋白在肾脏和其他器官中的作用和生理重要性。
Loutzenhiser and Aaronson1 argue that a lack of effect of amiloride and benzamil at 1 mol/L suggests that “[epithelial sodium channels] ENaC plays little if any role in myogenic signaling” in the afferent arteriole. They are correct. However, we do not hypothesize that the classical “ENaC channel”(formed by ENaC) is acting as a vascular mechanosensor. 1 We hypothesize the proteins that form ENaC channels (ie, ENaC and ENaC) in epithelial cells associate with related acid-sensing ion channel (ASIC) proteins to form a mechanosensor, 2 a very important distinction. We have use the Caenorhabditis elegans mechanosensor as a model for a mammalian vascular mechanosensor because ENaC proteins are related to proteins that form the pore of the C elegans mechanosensor. In this model, the mechanosensor is formed by an ion channel (ENaC-ASIC), which is tethered and gated by interactions with extracellular matrix and cytoskeleton proteins. 3 Because of a scarcity of approaches to silence vascular degenerins, broad-spectrum ENaC-ASIC inhibitors, such as amiloride, have been used initially to determine the importance of ENaC proteins as mediators of the myogenic response. Because of the predicted heteromeric nature of the mechanosensor and the potential influence of electrochemical gradient, protein modification, and splice variants on amiloride sensitivity, we did not expect the amiloride sensitivity of the myogenic response to match precisely with those of channels formed by ENaC proteins in expression systems and native epithelia. 4, 5 Thus, differences in amiloride specificity are expected because the vascular mechanosensor is not the classical ENaC channel. Loutzenhiser and Aaronson1 also suggest that,“Direct electrophysiological approaches may ultimately resolve this issue and determine whether a channel with the functional and pharmacological properties of ENaC is observed in afferent arteriolar myocytes.” Although it would be convenient to find an ENaC channel in vascular smooth muscle cells by electrophysiology, failure to find such a channel does not necessarily mean that ENaC proteins are not functional in vascular smooth muscle cells. C elegans literature suggests that the wild-type degenerin mechanosensor model is electrically silent. 3 Thus, an ENaC-containing mechanosensor is likely to be electrically silent. Then the question becomes whether the channel be gated. If the extracellular matrix is critical to gating the mechanosensor, as the model predicts, then preparing vascular smooth muscle cells for electrophysiological assessment by enzymatic dissociation destroys the extracellular matrix essential to gating. Thus, an electrically silent channel and no gating mechanism could easily explain the absence of electrophysiological evidence for the ENaC channel.Evidence for ENaC protein function will likely require the use of genetically modified animals. Progress in determining the importance of ENaC and ASIC proteins to myogenic responsiveness in genetically modified animals is underway. Recent studies indicate that mice with reduced levels of ENaC have altered myogenic responsiveness and blood flow autoregulation. 6 Although these studies suggest a role for ENaC/ASIC proteins in mediating myogenic constriction, more studies are needed to understand the role and physiological importance of ENaC/ASIC proteins in the kidney and other organs.