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Type: Journal article
Title: E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-β
Other Titles: E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta
Author: Wang, B.
Herman-Edelstein, M.
Koh, P.
Burns, W.
Jandeleit-Dahm, K.
Watson, A.
Saleem, M.
Goodall, G.
Twigg, S.
Cooper, M.
Kantharidis, P.
Citation: Diabetes, 2010; 59(7):1794-1802
Publisher: Amer Diabetes Assoc
Issue Date: 2010
ISSN: 0012-1797
Statement of
Bo Wang, Michal Herman-Edelstein, Philip Koh, Wendy Burns, Karin Jandeleit-Dahm, Anna Watson, Moin Saleem, Gregory J. Goodall, Stephen M. Twigg, Mark E. Cooper and Phillip Kantharidis
Abstract: OBJECTIVE--Increased deposition of extracellular matrix (ECM) within the kidney is driven by profibrotic mediators including transforming growth factor-[beta] (TGF-[beta]) and connective tissue growth factor (CTGF). We investigated whether some of their effects may be mediated through changes in expression of certain microRNAs (miRNAs). RESEARCH DESIGN AND METHODS--Proximal tubular cells, primary rat mesangial cells, and human podocytes were analyzed for changes in the expression of key genes, ECM proteins, and miRNA after exposure to TGF-[beta] (1-10 ng/[micro]l). Tubular cells were also infected with CTGF-adenovirus. Kidneys from diabetic apoE mice were also analyzed for changes in gene expression and miRNA levels. RESULTS--TGF-[beta] treatment was associated with morphologic and phenotypic changes typical of epithelial-mesenchymal transition (EMT) including increased fibrogenesis in all renal cell types and decreased E-cadherin expression in tubular cells. TGF-[beta] treatment also modulated the expression of certain miRNAs, including decreased expression of miR-192/215 in tubular cells, mesangial cells, which are also decreased in diabetic kidney. Ectopic expression of miR-192/215 increased E-cadherin levels via repressed translation of ZEB2 mRNA, in the presence and absence of TGF-[beta], as demonstrated by a ZEB2 3'-untranslated region luciferase reporter assay. However, ectopic expression of miR-192/215 did not affect the expression of matrix proteins or their induction by TGF-[beta]. In contrast, CTGF increased miR-192/215 levels, causing a decrease in ZEB2, and consequently increased E-cadherin mRNA. CONCLUSIONS--These data demonstrate the linking role of miRNA-192/215 and ZEB2 in TGF-[beta]/CTGF-mediated changes in E-cadherin expression. These changes appear to occur independently of augmentation of matrix protein synthesis, suggesting that a multistep EMT program is not necessary for fibrogenesis to occur.
Keywords: Kidney
Cells, Cultured
Cell Line
Epithelial Cells
Transforming Growth Factor beta
Blotting, Western
Reverse Transcriptase Polymerase Chain Reaction
Cell Shape
Gene Expression
Rights: © 2010 American Diabetes Association
DOI: 10.2337/db09-1736
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