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Cell Physiol Biochem. 2014;34(2):368-82. doi: 10.1159/000363006. Epub 2014 Jul 11.

Akt2 mediates TGF-β1-induced epithelial to mesenchymal transition by deactivating GSK3β/snail signaling pathway in renal tubular epithelial cells.

Author information

1
Beijing An Zhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Abstract

BACKGROUND:

The epithelial-mesenchymal transition (EMT) induced by growth factors or cytokines, particularly transforming growth factor-β (TGF-β1), plays an important role in kidney tubulointerstitial injury. However, signaling pathways mediating TGF-β1-induced EMT are not precisely known. In this study, we examined the role of Akt2 on EMT.

METHODS:

HK-2 cells were exposed to 10 ng/ml TGF-β1 to establish a model of EMT. The expression of proteins were detected by western blot assay and Immunofluorescence. The levels of genes were tested by RT-PCR.

RESULTS:

We found that treatment of HK-2 cells, a human proximal tubular cell line, with 10 ng/ml TGF-β1 resulted in activation of phosphatidylinositol 3-kinase (PI3K)/Akt2 signaling as evidenced by increased p-PI3K, Akt2 and p-Akt (Ser 473) expression. Importantly, TGF-β1 treatment decreased zona occludins 1 (ZO-1) and E-cadherin (epithelial markers) expression, increased fibronectin and vimentin (mesenchymal makers) expression, which were prevented by Ly294002 (the inhibitor of PI3K) or small interfering RNA (siAkt2), suggesting that Akt2 mediated TGF-β1-induced EMT. Meanwhile, RNA and protein levels of Snail1, the key inducer of EMT, were significantly elevated in TGF-β1-treated HK-2 cells. TGF-β1 also induced inactivation of glycogen synthase kinase-3β (GSK3β), an endogenous inhibitor of Snail. Knockdown of Akt2 using siRNAs or the PI3K inhibitor Ly294002 inhibited TGF-β1-induced phosphorylation of GSK3β and expression of Snail1.

CONCLUSION:

These findings revealed that knockdown of Akt2 antagonized TGF-β1-induced EMT by inhibiting GSK3β/Snail signaling pathway.

PMID:
25059120
DOI:
10.1159/000363006
[Indexed for MEDLINE]
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