The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia/reperfusion injury
The KCNE2 potassium channel β subunit is required for normal lung function and resilience to ischemia/reperfusion injury
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KCNE2 钾通道 β 亚基是正常肺功能和缺血/再灌注损伤恢复能力所必需的
DOI：
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Geoffrey W. Abbott
中科院分区：
文献类型：
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作者：
Leng Zhou;Clemens Köhnck;Zhaoyang Hu;Torsten K. Roepke;Geoffrey W. Abbott
kcnne2单跨膜电压门控钾（Kv）通道β亚基普遍表达，对多种细胞类型的正常功能至关重要，通常通过KCNQ1 Kv通道的调节。KCNE2上游多态性与人类肺功能下降有关，但KCNE2基因破坏对肺部的影响尚不清楚。在这里，小鼠Kcne2的种系缺失降低了钾通道α亚基Kcnq1和Kcnb1的肺表达，但没有改变其他Kcne基因的表达。Kcne2在小鼠肺中与Kcnq1共定位、共免疫沉淀，强烈提示肺部Kcnq1-Kcne2通道复合物的形成。Kcne2缺失降低了细支气管肺泡灌洗液中的血氧，增加了二氧化碳，增加了肺凋亡，增加了炎症介质TNF-α、IL-6和白细胞。与肺血管渗漏增加一致，Kcne2缺失增加了血浆白蛋白和BAL白蛋白，以及BAL/血浆白蛋白浓度比。Kcne2-/-小鼠肺表现出再灌注损伤挽救激酶（RISK）途径的基线诱导，但通过该途径对施加的肺缺血/再灌注损伤（IRI）的反应能力较弱。我们得出结论，KCNE2调节肺中的KCNQ1，是正常肺功能和肺IRI抵抗所必需的。我们的数据支持KCNE2基因破坏与肺功能障碍之间的因果关系。
The KCNE2 single transmembrane-spanning voltage-gated potassium (Kv) channel β subunit is ubiquitously expressed and essential for normal function of a variety of cell types, often via regulation of the KCNQ1 Kv channel. A polymorphism upstream of KCNE2 is associated with reduced lung function in human populations, but the pulmonary consequences of KCNE2 gene disruption are unknown. Here, germline deletion of mouse Kcne2 reduced pulmonary expression of potassium channel α subunits Kcnq1 and Kcnb1 but did not alter expression of other Kcne genes. Kcne2 co-localized and co-immunoprecipitated with Kcnq1 in mouse lung, strongly suggesting the formation of pulmonary Kcnq1-Kcne2 channel complexes. Kcne2 deletion reduced blood O2, increased CO2, increased pulmonary apoptosis, and increased inflammatory mediators TNF-α, IL-6 and leukocytes in bronchiolar alveolar lavage (BAL) fluids. Consistent with increased pulmonary vascular leakage, Kcne2 deletion increased plasma and BAL albumin, and the BAL/plasma albumin concentration ratio. Kcne2-/- mouse lungs exhibited baseline induction of the reperfusion injury salvage kinase (RISK) pathway but were less able to respond via this pathway to imposed pulmonary ischemia/reperfusion injury (IRI). We conclude that KCNE2 regulates KCNQ1 in the lungs and is required for normal lung function and resistance to pulmonary IRI. Our data support a causal relationship between KCNE2 gene disruption and lung dysfunction.