Notch mediated epithelial to mesenchymal transformation is associated with increased expression of the Snail transcription factor

Notch signalling pathway has been implicated as an important contributor to epithelial to myofibroblast transformation (EMT) in tumourigenesis. However, its role in kidney tubular cells undergoing EMT is not defined. This study assessed Notch signalling and the downstream effects on Snail in culture...

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Bibliographic Details
Published in:	The international journal of biochemistry & cell biology Vol. 42; no. 7; pp. 1115 - 1122
Main Authors:	Saad, S., Stanners, S.R., Yong, R., Tang, O., Pollock, C.A.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Ltd 01-07-2010
Subjects:	Actins - metabolism Angiotensin II - pharmacology Cadherins - metabolism Cell Transformation, Neoplastic - drug effects Cell Transformation, Neoplastic - metabolism Cell Transformation, Neoplastic - pathology Cells, Cultured Chronic kidney disease EMT Epithelial Cells - drug effects Epithelial Cells - metabolism Epithelium - drug effects Epithelium - metabolism Epithelium - pathology Gene Silencing - drug effects Humans Interstitial fibrosis Kidney Tubules - drug effects Kidney Tubules - metabolism Kidney Tubules - pathology Matrix Metalloproteinase 2 - metabolism Matrix Metalloproteinase 9 - metabolism Mesoderm - drug effects Mesoderm - metabolism Mesoderm - pathology Notch Protein Processing, Post-Translational - drug effects Protein Structure, Tertiary Receptors, Notch - chemistry Receptors, Notch - metabolism Snail Family Transcription Factors TGFβ Transcription Factors - metabolism Transforming Growth Factor beta1 - pharmacology TGFβ Chronic kidney disease EMT Interstitial fibrosis Notch
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Summary:	Notch signalling pathway has been implicated as an important contributor to epithelial to myofibroblast transformation (EMT) in tumourigenesis. However, its role in kidney tubular cells undergoing EMT is not defined. This study assessed Notch signalling and the downstream effects on Snail in cultured proximal tubular epithelial cells. EMT was induced by exposure to transforming growth factor beta-1 (TGFβ 1) and angiotensin II (AngII). The expressions of Notch1, Snail, E-cadherin and α-smooth muscle actin (α-SMA) were determined by Western blot. Matrix Metalloproteinase (MMP)-2 and -9 production were determined by zymography. The specific roles of Notch1-ICD and Snail were determined by gene expression or siRNA technique respectively. TGFβ 1 and AngII resulted in EMT as characterized by the expected decrease in E-cadherin expression, an increase in α-SMA, MMP-2 and MMP-9 expression and associated increase of Notch1 and Snail. Over-expression of Notch1-ICD similarly resulted in increased Snail expression, loss of E-cadherin and increasedα-SMA. Inhibiting Snail degradation by pre-treatment with lithium chloride (LiCl) led to a further decrease in E-cadherin expression in cells concurrently exposed to TGFβ 1 + AngII, confirming that Snail is a repressor of E-cadherin. Silencing of Snail blocked TGFβ 1 + AngII induced EMT. Inhibition of Notch activation, by concurrent exposure to DAPT during the induction of EMT attenuated the decrease in E-cadherin expression, limited the increase in α-SMA and MMP-2 and -9 expression and decreased Snail expression. These results suggest a direct role for Notch signalling via the Snail pathway in the development of EMT and renal fibrosis.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1357-2725 1878-5875
DOI:	10.1016/j.biocel.2010.03.016