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KMID : 0359920070260010034
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Korean Journal of Nephrology
2007 Volume.26 No. 1 p.34 ~ p.44
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Antifibrotic Effect of BMP-7 in the Peritoneum and the Mechanism
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Seo Ji-Yeon
Ha Hun-joo
Yu Mi-Ra
Kim Jae-Ryong
Ahn Myun-Whan
Lee Hi-Bahl
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Abstract
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Purpose: Bone morphogenic protein (BMP)-7, a member of TGF-β1 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-β1-induced epithelial-mesenchymal transition (EMT) of HPMC and in TGF-β1 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-β1 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 α-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-β1. Transfection of AdBMP-7 resulted in 2.5-fold increase in BMP-7mRNA expression in HPMC. TGF-β1 significantly decreased E-cadherin and increased α-SMA expression in GFP transfected cells. BMP-7 overexpression effectively reversed TGF-β1-induced Ecadherin and α-SMA expression and significantly suppressed TGF-β1-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-β1 may permit the development of peritoneal fibrosis during long-term PD. Our data demonstrate that BMP-7 overexpression reverses TGF-β1-induced EMT of HPMC and consequent peritoneal fibrosis possibly through inhibition of Smad2/3 and MAPK phosphorylation.
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KEYWORD
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Bone morphogenetic protein 7, Mitogen activated-protein kinase, Transforming growth factor-β1
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