Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation.
Chronic angiotensin II infusion drives extensive aldosterone-independent epithelial Na+ channel activation.
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DOI：
10.1161/hypertensionaha.113.01797
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Pochynyuk O
中科院分区：
文献类型：
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作者：
Mamenko M;Zaika O;Prieto MC;Jensen VB;Doris PA;Navar LG;Pochynyuk O
盐皮质激素受体（MR）阻断不能降低与高血管紧张素（Ang）II相关的高血压，提示Ang II通过醛固酮敏感性远端肾单位（ASDN）中的上皮Na+通道（ENaC）直接调节肾小管钠重吸收。我们使用从小鼠新鲜分离的ASDN来描述醛固酮和Ang II在控制功能性ENaC活性中的协同作用和首要作用。抑制MR特异性地阻止了由低钠饮食引起的功能活性ENaC数量的增加，但不能阻止ENaC开放概率的增加。与此相反，我们发现糖皮质激素受体（GR）在调节ENaC活性的饮食盐摄入量没有功能作用。同时抑制MR和血管紧张素II 1型受体（AT 1 R）改善了增强ENaC活性引起的低饮食盐摄入量，并产生显着更大的尿钠排泄比单独抑制剂。慢性全身性血管紧张素II输注诱导ENaC活性增加两倍以上，比在饮食钠限制期间观察到的。重要的是，ENaC活性在最大MR抑制期间保持大大高于对照水平。我们的结论是，在饮食中的盐摄入量的变化，醛固酮和血管紧张素II有助于补充ASDN的ENaC活性的调节。相反，在血管紧张素II依赖性高血压的情况下，ENaC活性上调远高于生理范围，并且不能通过抑制醛固酮-MR轴而有效抑制。这为肾内Ang II水平升高的高血压受试者对MR抑制的抵抗提供了机制解释。
The inability of mineralocorticoid receptor (MR) blockade to reduce hypertension associated with high Angiotensin (Ang) II suggests direct actions of Ang II to regulate tubular sodium reabsorption via the epithelial Na+ channel (ENaC) in the aldosterone-sensitive distal nephron (ASDN). We used freshly isolated ASDN from mice to delineate the synergism and primacy between aldosterone and Ang II in controlling functional ENaC activity. Inhibition of MR specifically prevented the increased number of functionally active ENaC but not ENaC open probability elicited by a low sodium diet. In contrast, we found no functional role of glucocorticoid receptors (GR) in the regulation of ENaC activity by dietary salt intake. Simultaneous inhibition of MR and Ang II type 1 receptors (AT1R) ameliorated the enhanced ENaC activity caused by low dietary salt intake and produced significantly greater natriuresis than either inhibitor alone. Chronic systemic Ang II infusion induced more than two times greater increase in ENaC activity than observed during dietary sodium restriction. Importantly, ENaC activity remained greatly above control levels during maximal MR inhibition. We conclude that during variations in dietary salt intake both aldosterone and Ang II contribute complementarily to the regulation of ENaC activity in the ASDN. In contrast, in the setting of Ang II-dependent hypertension, ENaC activity is up-regulated well above the physiological range and is not effectively suppressed by inhibition of the aldosterone-MR axis. This provides a mechanistic explanation for the resistance to MR inhibition that occurs in hypertensive subjects having elevated intrarenal Ang II levels.