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- Title
E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta.
- Authors
Wang B; Herman-Edelstein M; Koh P; Burns W; Jandeleit-Dahm K; Watson A; Saleem M; Goodall GJ; Twigg SM; Cooper ME; Kantharidis P; Wang, Bo; Herman-Edelstein, Michal; Koh, Philip; Burns, Wendy; Jandeleit-Dahm, Karin; Watson, Anna; Saleem, Moin; Goodall, Gregory J; Twigg, Stephen M
- Abstract
<bold>Objective: </bold>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).<bold>Research Design and Methods: </bold>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/microl). Tubular cells were also infected with CTGF-adenovirus. Kidneys from diabetic apoE mice were also analyzed for changes in gene expression and miRNA levels.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.
- Publication
Diabetes, 2010, Vol 59, Issue 7, p1794
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db09-1736