THE WNK4/SPAK PATHWAY STIMULATES ALVEOLAR FLUID CLEARANCE BY UPREGULATION OF EPITHELIAL SODIUM CHANNEL IN MICE WITH LIPOPOLYSACCHARIDE-INDUCED ACUTE RESPIRATORY DISTRESS SYNDROME

作者全名："Deng, Wang; Qi, Di; Tang, Xu-Mao; Deng, Xin-Yu; He, Jing; Wang, Dao-Xin"

作者地址："[Deng, Wang; Qi, Di; Tang, Xu-Mao; Deng, Xin-Yu; He, Jing; Wang, Dao-Xin] Chongqing Med Univ, Affiliated Hosp 2, Dept Resp & Crit Care Med, 76 Linjiang Rd, Chongqing 400010, Peoples R China; [Deng, Wang; Qi, Di; Tang, Xu-Mao; Deng, Xin-Yu; He, Jing; Wang, Dao-Xin] Chongqing Med Res Ctr Resp & Crit Care Med, Chongqing, Peoples R China"

通信作者："He, J; Wang, DX (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Resp & Crit Care Med, 76 Linjiang Rd, Chongqing 400010, Peoples R China."

来源：SHOCK

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000841921600009

JCR分区：Q1

影响因子：3.1

年份：2022

卷号：58

期号：1

开始页：68

结束页：77

文献类型：Article

关键词：Alveolar fluid clearance; acute respiratory distress syndrome; epithelial sodium channel; With-No lysine Kinases; Sterile 20-related proline-alanine-rich kinase

摘要："With-No lysine Kinases (WNKs) have been newly implicated in alveolar fluid clearance (AFC). Epithelial sodium channels (ENaCs) serve a vital role in AFC. The potential protective effect of WNK4 in acute respiratory distress syndrome (ARDS), mediated by ENaC-associated AFC was investigated in the study. A model of lipopolysaccharide (LPS)-induced ARDS was established in C57BL/6 mice. WNK4, Sterile 20-related proline-alanine-rich kinase (SPAK), small interfering RNA (siRNA)-WNK4 or siRNA-SPAK were transfected into mouse lung or primary alveolar epithelial type II (ATII) cells. AFC, bronchoalveolar lavage fluid and lung histomorphology were determined. The expression of ENaC was determined to investigate the regulation of AFC by WNK4-SPAK signaling pathway. Activation of WNK4-SPAK signaling improved lung injury and survival rate, with enhanced AFC and reduced pulmonary edema via the upregulation of ENaC in ARDS. In primary rat ATII cells, gene-silencing by siRNA transfection reduced ENaC expression and the level of WNK4-associated SPAK phosphorylation. Immunoprecipitation revealed that the level of neural precursor cell-expressed developmentally downregulated gene 4 (Nedd4-2) binding to ENaC was decreased as a result of WNK4-SPAK signaling. The present study demonstrated that the WNK4/SPAK pathway improved AFC during LPS-induced ARDS, which is mainly dependent on the upregulation of ENaC with Nedd4-2-mediated ubiquitination."

基金机构："National Natural Science Foundation of China [81600058, 81600060, 81670071]; Chongqing Natural Science Foundation [cstc2020jcyj-msxmX0008]; Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University [202124]"

基金资助正文："This work was supported by the National Natural Science Foundation of China (grant number: 81600058, 81600060, and 81670071), Chongqing Natural Science Foundation (cstc2020jcyj-msxmX0008), and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (grant no. 202124)."