BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury.
Bone morphogenic protein (BMP)-7 is a 35-kDa homodimeric protein and a member of the transforming growth factor (TGF)-beta superfamily. BMP-7 expression is highest in the kidney, and its genetic deletion in mice leads to severe impairment of eye, skeletal and kidney development. Here we report that BMP-7 reverses TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) by reinduction of E-cadherin, a key epithelial cell adhesion molecule. Additionally, we provide molecular evidence for Smad-dependent reversal of TGF-beta1-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-beta1-induced de novo EMT in a mouse model of chronic renal injury. 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-beta1 in the regulation of EMT in health and disease.
Zeisberg
Michael
M
Center for Matrix Biology, Gastroenterology and Renal Divisions, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Hanai
Jun-ichi
J
Sugimoto
Hikaru
H
Mammoto
Tadanori
T
Charytan
David
D
Strutz
Frank
F
Kalluri
Raghu
R
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology*; D015820:Cadherins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects / Q000196:embryology; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009393:Nephritis / Q000188:drug therapy* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051900:Smad3 Protein; D051902:Smad5 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D015820:Cadherins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I