Antifibrotic Effect of BMP-7 in the Peritoneum and the Mechanism.
- Author:
Ji Yeon SEO
1
;
Hunjoo HA
;
Mi Ra YU
;
Jae Ryong KIM
;
Myun Whan AHN
;
Hi Bahl LEE
Author Information
1. Hyonam Kidney Laboratory, Soon Chun Hyang University, Korea. hblee@hkl.ac.kr
- Publication Type:Original Article
- Keywords:
Bone morphogenetic protein 7;
Mitogen activated-protein kinase;
Transforming growth factor-beta1
- MeSH:
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
- From:Korean Journal of Nephrology
2007;26(1):34-44
- CountryRepublic of Korea
- Language:Korean
-
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.
