Korean J Nephrol.  2007 Jan;26(1):34-44.

Antifibrotic Effect of BMP-7 in the Peritoneum and the Mechanism

• Seo JY
• Ha H
• Yu MR
• Kim JR
• Ahn MW
• Lee HB

Abstract

PURPOSE: Bone morphogenic protein (BMP)-7, a member of TGF-beta1 superfamily, is an endogenous antifibrotic protein highly expressed in normal kidney. It is not known, however, whether human peritoneal mesothelial cells (HPMC) express BMP-7 or if BMP-7 protects against peritoneal fibrosis and by what mechanism. We examined the effect of BMP-7 overexpression in TGF-beta1-induced epithelial-mesenchymal transition (EMT) of HPMC and in TGF-beta1 signaling in HPMC to elucidate the mechanisms of antifibrotic effect of BMP-7.
METHODS
Growth arrested and synchronized HPMC were stimulated with 2 ng/mL of TGF-beta1 to induce EMT. HPMC were transiently transfected with adenovirus-mediated human BMP-7 (AdBMP-7) or with GFP (AdGFP). EMT was defined as downregulation of E-cadherin and upregulation of alpha-smooth muscle actin (SMA).
RESULTS
HPMC constitutively expressed BMP-7 mRNA and protein. BMP-7 mRNA and protein expression were significantly inhibited by 50 mM D-glucose, 2x diluted commercial peritoneal dialysis solution, and 2 ng/ml of TGF-beta1. Transfection of AdBMP-7 resulted in 2.5-fold increase in BMP-7 mRNA expression in HPMC. TGF-beta1 significantly decreased E-cadherin and increased alpha-SMA expression in GFP transfected cells. BMP-7 overexpression effectively reversed TGF-beta1-induced E-cadherin and alpha-SMA expression and significantly suppressed TGF-beta1-induced phosphorylation of Smad2/3, ERK1/2, JNK, and p38 MAPK in HPMC as compared to GFP transfected cells.
CONCLUSION
BMP-7 is an endogenous antifibrotic protein and downregulation of BMP-7 in HPMC by high glucose, PD solution, and TGF-beta1 may permit the development of peritoneal fibrosis during long-term PD. Our data demonstrate that BMP-7 overexpression reverses TGF-beta1-induced EMT of HPMC and consequent peritoneal fibrosis possibly through inhibition of Smad2/3 and MAPK phosphorylation.

Keyword

Bone morphogenetic protein 7; Mitogen activated-protein kinase; Transforming growth factor-beta1

MeSH Terms

Actins
Bone Morphogenetic Protein 7*
Cadherins
Down-Regulation
Epithelial-Mesenchymal Transition
Glucose
Humans
Kidney
p38 Mitogen-Activated Protein Kinases
Peritoneal Dialysis
Peritoneal Fibrosis
Peritoneum*
Phosphorylation
RNA, Messenger
Transfection
Transforming Growth Factor beta1
Up-Regulation
Actins
Bone Morphogenetic Protein 7
Cadherins
Glucose
RNA, Messenger
Transforming Growth Factor beta1
p38 Mitogen-Activated Protein Kinases