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BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury

Abstract

Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-β 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-β1–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-β1–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-β1–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-β1 in the regulation of EMT in health and disease.

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Figure 1: E-cadherin expression in renal tubular epithelial cells.
Figure 2: Regulation of E-cadherin promoter activity.
Figure 3: Reversal of chronic renal injury by BMP-7 in mouse NTN.
Figure 4: Smad-associated reversal of EMT in vivo.

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Acknowledgements

This study was supported by National Institutes of Health grants DK 51711, DK 55001, T32 DK07199-25, Deutsche Forschungsgemeinschaft grant DFG ZE523/1-1 (to M.Z.) and Beth Israel Deaconess Medical Center funds associated with the Center for Matrix Biology. We thank Creative Biomolecules/Curis, Inc. for the recombinant human BMP-7; V.P. Sukhatme for introducing us to Creative Biomolecules/Curis, Inc. when he served as their consultant; and L. Siniski and A. Zuk for their help with the preparation of this manuscript; F.S. was a visiting scientist at Beth Israel Deaconess Medical Center and Harvard Medical School during the course of this study.

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Correspondence to Raghu Kalluri.

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Zeisberg, M., Hanai, Ji., Sugimoto, H. et al. BMP-7 counteracts TGF-β1–induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9, 964–968 (2003). https://doi.org/10.1038/nm888

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