HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/F1238    most recent 90539.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Veerasamy, M. Articles by Dockrell, M. E. C. PubMed PubMed Citation Articles by Veerasamy, M. Articles by Dockrell, M. E. C.

Differential regulation of E-cadherin and -smooth muscle actin by BMP 7 in human renal proximal tubule epithelial cells and its implication in renal fibrosis

¹South West Thames Institute for Renal Research, Epsom and St. Helier University Hospitals NHS Trust, Carshalton, United Kingdom; and ; ²Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands

Submitted September 8, 2008 ; accepted in final form September 4, 2009

Chronic kidney diseases are characterized by progressive tubulointerstitial fibrosis, and TGFβ1 plays a crucial role in its development. Bone morphogenic protein 7 (BMP 7), another member of the TGF superfamily, antagonized the profibrotic effects of TGFβ1, including epithelial mesenchymal transition and E-cadherin loss, in the previous studies from animal models. We investigated the effect of BMP 7 on TGFβ1-mediated E-cadherin loss in two different transformed human adult proximal tubule epithelia. We found that BMP 7 not only failed to prevent TGFβ1-mediated E-cadherin loss but itself downregulated E-cadherin levels and that it had an additive effect with TGFβ1 in inducing E-cadherin loss. The downregulation of E-cadherin by BMP 7 was mediated through the Smad1/5 pathway. BMP 7-mediated E-cadherin loss was not followed by de novo -smooth muscle actin (-SMA) expression (a marker of myofibroblastic phenotype), which was due to the concurrent induction of Inhibitor of DNA binding 1 (Id1, a basic helix loop helix class transcriptional regulator) through a non-Smad pathway. Concurrent treatment of BMP 7 and TGFβ1 prevented TGFβ1-mediated -SMA induction. In summary, our results suggest that E-cadherin loss, the key feature of epithelial mesenchymal transition, will not necessarily be followed by total phenotype change; rather, cells may undergo some loss of phenotypic marker in a ligand-dependent manner and participate in reparative processes. The inhibition of de novo expression of -SMA could explain the antifibrotic effect of BMP 7. Id1 might play a crucial role in maintaining proximal tubule epithelial cell phenotype and its signaling regulation could be a potential therapeutic target.

BMP 7; E-cadherin; renal proximal tubule epithelia; -smooth muscle actin