Insulin ameliorates pulmonary edema through the upregulation of epithelial sodium channel via the PI3K/SGK1 pathway in mice with lipopolysaccharide-induced lung injury
Insulin ameliorates pulmonary edema through the upregulation of epithelial sodium channel via the PI3K/SGK1 pathway in mice with lipopolysaccharide-induced lung injury
复制标题
胰岛素通过 PI3K/SGK1 通路上调上皮钠通道改善脂多糖诱导的肺损伤小鼠的肺水肿
DOI：
10.3892/mmr.2019.9809
复制
发表时间：
2019-03-01
影响因子：
3.4
通讯作者：
Wang, Dao-Xin
中科院分区：
文献类型：
--
作者：
Deng, Wang;Li, Chang-Yi;Wang, Dao-Xin
上皮钠通道（Epithelial sodium channel, ENaC）为急性肺损伤（ALI）肺泡间隙水肿的清除提供动力。我们之前的研究报道了胰岛素增加-ENaC的表达，可能是通过ALI的血清/糖皮质激素诱导激酶-1 （SGK1）途径；然而，SGK1活性的上游调控因子尚不清楚。在本研究中，C3H/HeN小鼠遭受脂多糖（LPS）诱导的无高血糖肺损伤。使用微渗透泵静脉注射外源性胰岛素，并气管内递送SGK1小干扰RNA （siRNA）。此外，转染了磷脂酰肌醇3-激酶（PI3K） siRNA或SGK1 siRNA的肺泡上皮II型细胞与胰岛素孵育。胰岛素保护肺上皮屏障，减少肺泡上皮细胞凋亡，减轻肺水肿，改善肺泡液清除率，增加小鼠-、-和- enac的表达水平。此外，在肺泡上皮细胞中，胰岛素增加-，-和- enac的表达水平，以及磷酸化的SGK1的表达水平，然后通过siRNA选择性靶向PI3K或SGK1来抑制。综上所述，本研究结果表明，在lps诱导的肺损伤中，胰岛素通过PI3K/SGK1通路上调ENaC，从而保护肺上皮，减轻肺水肿。
Epithelial sodium channel (ENaC) provides the driving force for the removal of edema from the alveolar spaces in acute lung injury (ALI). Our previous study reported that insulin increased the expression of -ENaC, possibly via the serum/glucocorticoid-inducible kinase-1 (SGK1) pathway in ALI; however, the upstream regulator of SGK1 activity remains unclear. In the current study, C3H/HeN mice were subjected to lipopolysaccharide (LPS)-induced lung injury without hyperglycemia. Exogenous insulin was administered intravenously using a micro-osmotic pump, and intratracheal delivery of SGK1 small interfering RNA (siRNA) was performed. Furthermore, alveolar epithelial type II cells transfected with phosphatidylinositol 3-kinase (PI3K) siRNA or SGK1 siRNA were incubated with insulin. Insulin protected the pulmonary epithelial barrier, reduced the apoptosis of alveolar epithelial cells, attenuated pulmonary edema, improved alveolar fluid clearance, and increased the expression levels of -, - and -ENaC in mice. In addition, in alveolar epithelial cells, insulin increased the expression levels of -, - and -ENaC, as well as the level of phosphorylated SGK1, which were then inhibited by the selective targeting of PI3K or SGK1 by siRNA. Taken together, the results of the present study demonstrated that insulin protected the lung epithelium and attenuated pulmonary edema through the upregulation of ENaC via the PI3K/SGK1 pathway in LPS-induced lung injury.