Insulin upregulates the expression of epithelial sodium channel in vitro and in a mouse model of acute lung injury: role of mTORC2/SGK1 pathway.

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by proteinaceous pulmonary edema and severe arterial hypoxemia with a mortality of approximately 40%. Stimulation of epithelial sodium channel (ENaC) promotes Na(+) transport, a rate-limiting step for pulmonary edema reabsorption. Insulin is known to participate in the ion transport; however, its role in pulmonary edema clearance and the regulatory mechanism involved have not been fully elucidated. In the current study, in a lipopolysaccharide-based mouse model of ALI, we found that insulin alleviated pulmonary edema by promoting ENaC-mediated alveolar fluid clearance through serum and glucocorticoid induced kinase-1 (SGK1). In alveolar epithelial cells, insulin increased the expression of α-, β-, and γ-ENaC, which was blocked by the mammalian target of rapamycin complex 2 (mTORC2) inhibitor or knockdown of Rictor (a necessary component of mTORC2), and SGK1 inhibitor, respectively. In addition, an immunoprecipitation study demonstrated that SGK1(Ser422) phosphorylation, the key step for complete SGK1 activation by insulin, was conducted through PI3K/mTORC2 pathway. Finally, we testified the role of mTORC2 in vivo by demonstrating that PP242 prevented insulin-stimulated SGK1 activation and ENaC increase during ALI. The data revealed that during ALI, insulin stimulates alveolar fluid clearance by upregulating the expression of α-, β-, and γ-ENaC at the cell surface, which was, at least, partially through activating mTROC2/SGK1 signaling pathway.

• Authors: Jing He, Di Qi, Dao-Xin Wang, Wang Deng, Yuan Ye, Long-Hua Feng, Tao Zhu, Yan Zhao, Chun-Rong Zhang
• Journal: Experimental cell research (Exp Cell Res) Vol. 331 Issue 1 Pg. 164-175 (Feb 01 2015) ISSN: 1090-2422 [Electronic] United States
• PMID: 25265063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Epithelial Sodium Channels
• Hypoglycemic Agents
• Immediate-Early Proteins
• Insulin
• Multiprotein Complexes
• RNA, Messenger
• Mechanistic Target of Rapamycin Complex 2
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Acute Lung Injury (drug therapy, metabolism, pathology)
• Animals
• Blotting, Western
• Disease Models, Animal
• Epithelial Sodium Channels (genetics, metabolism)
• Humans
• Hypoglycemic Agents (pharmacology)
• Immediate-Early Proteins (genetics, metabolism)
• Immunoenzyme Techniques
• Immunoprecipitation
• In Vitro Techniques
• Insulin (pharmacology)
• Male
• Mechanistic Target of Rapamycin Complex 2
• Mice
• Mice, Inbred C57BL
• Multiprotein Complexes (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Pulmonary Alveoli (drug effects, metabolism, pathology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (genetics, metabolism)
• Up-Regulation