Epithelial sodium channel is a key mediator of growth hormone-induced sodium retention in acromegaly
Epithelial sodium channel is a key mediator of growth hormone-induced sodium retention in acromegaly
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DOI：
10.1210/en.2008-0143
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发表时间：
2008-07-01
期刊：
影响因子：
4.8
通讯作者：
Lombes, Marc
中科院分区：
文献类型：
--
作者：
Kamenicky, Peter;Viengchareun, Say;Lombes, Marc
肢端肥大症患者存在容量扩张和动脉高压，但GH直接抗利尿作用的肾脏部位和分子机制仍不清楚。在这里，我们表明，肢端肥大症GC大鼠，这是长期暴露于非常高的GH水平，表现出减少呋塞米诱导的尿钠排泄和增加阿米洛利刺激的尿钠排泄与对照组相比。增强Na+，K+-ATP酶活性和改变上皮钠通道（ENaC）亚单位在皮质集合管（CCD）的GC大鼠蛋白水解成熟提供了额外的证据，增加钠重吸收的晚期远端肾单位慢性GH过量。在小鼠CCD细胞模型KC 3AC 1细胞上的体外实验揭示了功能性GH受体和IGF-I受体的表达与Janus激酶信号转导子和转录激活子5、ERK和AKT信号通路的激活偶联。GH直接控制CCD细胞中的钠重吸收得到以下支持：1）刺激由GH受体拮抗剂pegvisomant抑制的跨上皮钠转运; 2）诱导α-ENaC mRNA表达; 3）鉴定与位于α-ENaC启动子中的反应元件结合的信号转导子和转录激活子5，表明GH对α-ENaC的转录调控。我们的研究结果提供了第一个证据表明，生长激素，在音乐会与IGF-I，刺激ENaC介导的钠转运在晚期远端肾单位，占发病机制的钠潴留肢端肥大症。
Acromegalic patients present with volume expansion and arterial hypertension, but the renal sites and molecular mechanisms of direct antinatriuretic action of GH remain unclear. Here, we show that acromegalic GC rats, which are chronically exposed to very high levels of GH, exhibited a decrease of furosemide-induced natriuresis and an increase of amiloride-stimulated natriuresis compared with controls. Enhanced Na+, K+-ATPase activity and altered proteolytic maturation of epithelial sodium channel ( ENaC) subunits in the cortical collecting ducts (CCDs) of GC rats provided additional evidence for an increased sodium reabsorption in the late distal nephron under chronic GH excess. In vitro experiments on KC3AC1 cells, a murine CCD cell model, revealed the expression of functional GH receptors and IGF-I receptors coupled to activation of Janus kinase signal transducer and activator of transcription 5, ERK, and AKT signaling pathways. That GH directly controls sodium reabsorption in CCD cells is supported by: 1) stimulation of transepithelial sodium transport inhibited by GH receptor antagonist pegvisomant; 2) induction of alpha-ENaC mRNA expression; and 3) identification of signal transducer and activator of transcription 5 binding to a response element located in the alpha-ENaC promoter, indicative of the transcriptional regulation of alpha-ENaC by GH. Our findings provide the first evidence that GH, in concert with IGF-I, stimulates ENaC-mediated sodium transport in the late distal nephron, accounting for the pathogenesis of sodium retention in acromegaly.