title: MicroRNA 16 modulates epithelial sodium channel in human alveolar epithelial cells.
abstract: Acute lung injury (ALI) is a devastating disease characterized by pulmonary edema. Removal of edema from the air spaces of lung is a critical function of the epithelial sodium channel (ENaC) in ALI. The molecular mechanisms behind resolution of pulmonary edema are incompletely understood. MicroRNA's (miRNA) are crucial gene regulators and are dysregulated in various diseases including ALI. Recent studies suggest that microRNA-16 (miR-16) targets serotonin transporter (SERT) involved in the serotonin (5-HT) transmitter system. Alterations in serotonin levels have been reported in various pulmonary diseases. However, the role of miR-16 on its target SERT, and ENaC, a key ion channel involved in the resolution of pulmonary edema, have not been studied. In the present study, the expression patterns of miR-16, SERT, ENaC and serotonin were investigated in mice exposed to room air and hyperoxia. The effects of miR-16 overexpression on ENaC, SERT, TGF-β and Nedd4 in human alveolar epithelial cells were analyzed. miR-16 and ENaC were downregulated in mice exposed to hyperoxia. miR-16 downregulation in mouse lung was correlated with an increase in SERT expression and pulmonary edema. Overexpression of miR-16 in human alveolar epithelial cells (A549) suppressed SERT and increased ENaCβ levels when compared to control-vector transfected cells. In addition, miR-16 over expression suppressed TGFβ release, a critical inhibitor of ENaC. Interestingly Nedd4, a negative regulator of ENaC remained unaltered in miR-16 over expressed A549 cells when compared to controls. Taken together, our data suggests that miR-16 upregulates ENaC, a major sodium channel involved in resolution of pulmonary edema in ALI.
authors.affiliation: Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC 19, Tampa, FL 33612, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Tamarapu Parthasarathy
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Galam
authors.forename: Bao
authors.initials: B
authors.lastname: Huynh
authors.forename: Asfiya
authors.initials: A
authors.lastname: Yunus
authors.forename: Toaa
authors.initials: T
authors.lastname: Abuelenen
authors.forename: Annie
authors.initials: A
authors.lastname: Castillo
authors.forename: Gurukumar
authors.initials: G
authors.lastname: Kollongod Ramanathan
authors.forename: Ruan
authors.initials: R
authors.lastname: Cox
authors.forename: Narasaiah
authors.initials: N
authors.lastname: Kolliputi
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism*; D000332:Aerobiosis; D000818:Animals; D045744:Cell Line, Tumor; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D011650:Pulmonary Alveoli / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D053503:Epithelial Sodium Channels; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; C507048:SCNN1B protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D016211:Transforming Growth Factor alpha; D012701:Serotonin; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases