Bone marrow mesenchymal stem cells derived miRNA-130b enhances epithelial sodium channel by targeting PTEN
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RESEARCH
Bone marrow mesenchymal stem cells derived miRNA‑130b enhances epithelial sodium channel by targeting PTEN Honglei Zhang†, Yan Ding†, Yapeng Hou, Yanhong Liu, Zhiyu Zhou and Hongguang Nie*
Abstract Aims: Acute lung injury (ALI) is a clinical syndrome with high morbidity and mortality, and severe pulmonary edema is one of the characteristics. Epithelial sodium channel (ENaC) located on the apical side of alveolar type 2 epithelial (AT2) cells is the primary rate limiting segment in alveolar fluid clearance. Many preclinical studies have revealed that mesenchymal stem cells (MSCs) based therapy has great therapeutic potential for ALI, while the role of ENaC in this process is rarely known. Methods: We studied the effects of bone marrow-derived MSCs (BMSCs) on the protein/mRNA expression and activity of ENaC in primary mouse AT2 and human H441 cells by co-culture with them, respectively. Moreover, the changes of miRNA-130b in AT2 cells were detected by qRT-PCR, and we studied the involvement of phosphatase and tensin homolog deleted on chromosome ten (PTEN) and the downstream PI3K/AKT pathway in the miRNA-130b regulation of ENaC. Results: Our results demonstrated that BMSCs could increase ENaC protein expression and function, as well as the expression level of miRNA-130b. The dual luciferase target gene assay verified that PTEN was one of the target genes of miR-130b, which showed adverse effects on the protein expression of α/γ-ENaC and PTEN in AT2 cells. Upregulating miR-130b and/or knocking down PTEN resulted in the increase of α/γ-ENaC protein level, and the protein expression of p-AKT/AKT was enhanced by miR-130b. Both α and γ-ENaC protein expressions were increased after AT2 cells were transfected with siPTEN, which could be reversed by the co-administration of PI3K/AKT inhibitor LY294002. Conclusion: In summary, miRNA-130b in BMSCs can enhance ENaC at least partially by targeting PTEN and activating PI3K/AKT pathway, which may provide a promising new direction for therapeutic strategy in ALI. Keywords: Epithelial sodium channel, Bone marrow mesenchymal stem cells, miRNA-130b, Acute lung injury Introduction Acute lung injury (ALI) is a common clinical syndrome with high morbidity and mortality caused by sepsis, pneumonia, trauma, etc. [1, 2]. ALI and acute respiratory distress syndrome (ARDS) are characterized by *Correspondence: [email protected] † Honglei Zhang and Yan Ding contribute equally to this work Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, People’s Republic of China
an inflammatory response, alveolar edema, and hypoxemia. Approximately 40% of the ALI/ARDS patients are linked with viral and bacterial pneumonia [3, 4]. Lipopolysaccharide (LPS) is widely used to induce ALI models, which can attack pulmonary microvascular endothelial cells, and result in leakage of proteinrich edema fluid related with pulmonary endothelial cell injury, barrier dysfunction and inflammation [5]. Enhanced alveola
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