Bone Morphogenetic Protein-2 Antagonizes Renal Interstitial Fibrosis by Promoting Catabolism of Type I Transforming Growth Factor-β Receptors

TGF-β is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-β to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-β superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2009-02, Vol.150 (2), p.727-740
Main Authors: Yang, Yu-Lin, Liu, Yi-Shiuan, Chuang, Lea-Yea, Guh, Jinn-Yuh, Lee, Tao-Chen, Liao, Tung-Nan, Hung, Min-Yuan, Chiang, Tai-An
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Bone Morphogenetic Protein 2 - genetics
Bone Morphogenetic Protein 2 - pharmacology
Bone Morphogenetic Protein 2 - physiology
Cells, Cultured
Cytoprotection - drug effects
Cytoprotection - genetics
Fibrosis - genetics
Fundamental and applied biological sciences. Psychology
Humans
Kidney - drug effects
Kidney - metabolism
Kidney - pathology
Kidney Diseases - genetics
Kidney Diseases - metabolism
Kidneys
Male
Medical sciences
Metabolism - drug effects
Metabolism - genetics
Nephrology. Urinary tract diseases
Protein-Serine-Threonine Kinases - metabolism
Rats
Rats, Sprague-Dawley
Rats, Transgenic
Receptors, Transforming Growth Factor beta - metabolism
Transforming Growth Factor beta1 - pharmacology
Ureteral Obstruction - complications
Ureteral Obstruction - genetics
Ureteral Obstruction - metabolism
Ureteral Obstruction - pathology
Urinary system involvement in other diseases. Miscellaneous
Vertebrates: endocrinology
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Summary:TGF-β is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-β to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-β superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-β1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-β1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-β receptors (TGF-β RI). Moreover, BMP-2 significantly shortened the half-life of TGF-β RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-β RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-β RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-β. We demonstrated that BMP-2 significantly reversed the TGF-β1-induced increase in pSmad2/3 and reversed the TGF-β1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-β RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson’s trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-β RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-β RI and Smads. Bone morphogenetic protein-2 can antagonize TGF-β-inducing cellular fibrosis by intervening post-receptors signaling, thus disclosing an application of therapeutical potential against fibrosis disorders.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2008-0090