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

Veerasamy M, Nguyen TQ, Motazed R, Pearson AL, Goldschmeding R, Dockrell ME. Differential regulation of E-cadherin and alpha-smooth muscle actin by BMP 7 in human renal proximal tubule epithelial cells and its implication in renal fibrosis. Am J Physiol Renal Physiol 297: F1238-F1248, 2009. First published September 9, 2009; doi: 10.1152/ajprenal.90539.2008.-Chronic kidney diseases are characterized by progressive tubulointerstitial fibrosis, and TGF beta 1 plays a crucial role in its development. Bone morphogenic protein 7 (BMP 7), another member of the TGF superfamily, antagonized the profibrotic effects of TGF beta 1, including epithelial mesenchymal transition and E-cadherin loss, in the previous studies from animal models. We investigated the effect of BMP 7 on TGF beta 1-mediated E-cadherin loss in two different transformed human adult proximal tubule epithelia. We found that BMP 7 not only failed to prevent TGF beta 1-mediated E-cadherin loss but itself downregulated E-cadherin levels and that it had an additive effect with TGF beta 1 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 alpha-smooth muscle actin (alpha-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 TGF beta 1 prevented TGF beta 1-mediated alpha-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 alpha-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.