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.
Chronic kidney diseases are characterized by progressive tubulointerstitial fibrosis, and TGFbeta1 plays a crucial role in its development. Bone morphogenic protein 7 (BMP 7), another member of the TGF superfamily, antagonized the profibrotic effects of TGFbeta1, including epithelial mesenchymal transition and E-cadherin loss, in the previous studies from animal models. We investigated the effect of BMP 7 on TGFbeta1-mediated E-cadherin loss in two different transformed human adult proximal tubule epithelia. We found that BMP 7 not only failed to prevent TGFbeta1-mediated E-cadherin loss but itself downregulated E-cadherin levels and that it had an additive effect with TGFbeta1 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 TGFbeta1 prevented TGFbeta1-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.
Veerasamy
Mangalakumar
M
South West Thames Institute for Renal Research, Epsom and St. Helier University Hospitals NHS Trust, Carshalton, United Kingdom. vmangalakumar1@hotmail.com
Nguyen
Tri Q
TQ
Motazed
Reza
R
Pearson
Alexander L
AL
Goldschmeding
Roel
R
Dockrell
Mark E C
ME
D000199:Actins / Q000096:biosynthesis*; D000328:Adult; D015153:Blotting, Western; D055419:Bone Morphogenetic Protein 7 / Q000494:pharmacology*; D015820:Cadherins / Q000096:biosynthesis*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D005355:Fibrosis / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D051898:Smad1 Protein / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000502:physiology; D014404:Tubulin / Q000096:biosynthesis
D000199:Actins; D055419:Bone Morphogenetic Protein 7; D015820:Cadherins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D034741:RNA, Small Interfering; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D053773:Transforming Growth Factor beta1; D014404:Tubulin