Aldosterone responsiveness of the epithelial sodium channel (ENaC) in colon is increased in a mouse model for Liddle's syndrome
Aldosterone responsiveness of the epithelial sodium channel (ENaC) in colon is increased in a mouse model for Liddle's syndrome
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DOI：
10.1113/jphysiol.2007.140459
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发表时间：
2008-01-15
影响因子：
5.5
通讯作者：
Korbmacher, Christoph
中科院分区：
文献类型：
--
作者：
Bertog, Marko;Cuffe, John E.;Korbmacher, Christoph
Liddle综合征是人类高血压的常染色体显性形式，由上皮钠通道（ENaC）的功能获得性突变引起，其在包括远端结肠的醛固酮靶组织中表达。我们使用Liddle综合征小鼠模型，通过测量阿米洛利敏感性跨上皮短路电流（Delta ISC-Ami）体外研究ENaC介导的晚期远端结肠Na+转运。在维持标准盐饮食的Liddle小鼠中，Delta ISC-Ami仅略微增加，但血浆醛固酮（P-Aldo）受到严重抑制。Liddle小鼠通过分别增加或减少其P-Aldo和Delta ISC-Ami对低盐或高盐饮食作出反应。然而，在Liddle动物中需要较少的醛固酮来实现与野生型动物相似甚至更高的Na+转运速率。事实上，醛固酮刺激Delta ISC-Ami的能力在Liddle动物中比野生型对照动物高约三倍。醛固酮在体外结肠组织中的应用证实，醛固酮对Liddle小鼠ENaC的刺激不仅被保留，而且被增强。在Liddle和野生型动物的结肠组织中，醛固酮诱导的通道β和γ亚基（β ENaC和γ ENaC）以及血清和糖皮质激素诱导型激酶I（SGK 1）的转录上调相似，而醛固酮对α亚基（α ENaC）没有转录作用。此外，Na+反馈调节在很大程度上保留在Liddle动物的结肠组织中。总之，我们已经证明，在Liddle小鼠的结肠中，ENaC介导的Na+转运随着对醛固酮的反应性增加而增强。这可能与Liddle综合征患者的病理生理相关，特别是在高盐饮食中，当抑制P-Aldo可能不足以将Na+吸收降低到适当水平时。
Liddle's syndrome is an autosomal dominant form of human hypertension, caused by gain-of-function mutations of the epithelial sodium channel (ENaC) which is expressed in aldosterone target tissues including the distal colon. We used a mouse model for Liddle's syndrome to investigate ENaC-mediated Na+ transport in late distal colon by measuring the amiloride-sensitive transepithelial short circuit current (Delta ISC-Ami) ex vivo. In Liddle mice maintained on a standard salt diet, Delta ISC-Ami was only slightly increased but plasma aldosterone (P-Aldo) was severely suppressed. Liddle mice responded to a low or a high salt diet by increasing or decreasing, respectively, their P-Aldo and Delta ISC-Ami. However, less aldosterone was required in Liddle animals to achieve similar or even higher Na+ transport rates than wild-type animals. Indeed, the ability of aldosterone to stimulate Delta ISC-Ami was about threefold higher in Liddle animals than in the wild-type controls. Application of aldosterone to colon tissue in vitro confirmed that ENaC stimulation by aldosterone was not only preserved but enhanced in Liddle mice. Aldosterone-induced transcriptional up-regulation of the channel's beta- and gamma-subunit (beta ENaC and gamma ENaC) and of the serum- and glucocorticoid-inducible kinase I (SGK1) was similar in colon tissue from Liddle and wild-type animals, while aldosterone had no transcriptional effect on the alpha-subunit (alpha ENaC). Moreover, Na+ feedback regulation was largely preserved in colon tissue of Liddle animals. In conclusion, we have demonstrated that in the colon of Liddle mice, ENaC-mediated Na+ transport is enhanced with an increased responsiveness to aldosterone. This may be pathophysiologically relevant in patients with Liddle's syndrome, in particular on a high salt diet, when suppression of P-Aldo is likely to be insufficient to reduce Na+ absorption to an appropriate level.