Nature Medicine9, 964 - 968 (2003)
Published online: 15 June 2003; | doi:10.1038/nm888
BMP-7 counteracts TGF-1−induced epithelial-to-mesenchymal transition and reverses chronic renal injury
Michael Zeisberg1, 2, Jun-ichi Hanai1, 2, Hikaru Sugimoto1, Tadanori Mammoto1, David Charytan1, Frank Strutz1
& Raghu Kalluri1
1
Center for Matrix Biology, Gastroenterology and Renal Divisions, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)- superfamily1. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development2. Here we report that BMP-7 reverses TGF-1−induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule3. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-1−induced EMT by BMP-7 in renal tubular epithelial cells and mammary ductal epithelial cells. In the kidney, EMT-induced accumulation of myofibroblasts and subsequent tubular atrophy are considered key determinants of renal fibrosis during chronic renal injury. We therefore tested the potential of BMP-7 to reverse TGF-1−induced de novo EMT in a mouse model of chronic renal injury4. Our results show that systemic administration of recombinant human BMP-7 leads to repair of severely damaged renal tubular epithelial cells, in association with reversal of chronic renal injury. Collectively, these results provide evidence of cross talk between BMP-7 and TGF-1 in the regulation of EMT in health and disease.
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1−induced epithelial-to-mesenchymal transition and reverses chronic renal injury
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