BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury

Nat Med. 2003 Jul;9(7):964-8. doi: 10.1038/nm888.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism
  • Animals
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins / metabolism
  • Bone Morphogenetic Proteins / pharmacology*
  • Cadherins / drug effects
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Chronic Disease
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / physiology
  • Kidney Tubules / cytology*
  • Kidney Tubules / drug effects
  • Kidney Tubules / embryology
  • Mesoderm / cytology*
  • Mesoderm / drug effects
  • Mesoderm / metabolism
  • Mice
  • Mice, Inbred Strains
  • Nephritis / drug therapy*
  • Nephritis / pathology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction
  • Smad3 Protein
  • Smad5 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transfection
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1

Substances

  • BMP7 protein, human
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins
  • Cadherins
  • DNA-Binding Proteins
  • Phosphoproteins
  • Receptors, Transforming Growth Factor beta
  • Recombinant Proteins
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad5 Protein
  • Smad5 protein, mouse
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I