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

• DOI: 10.1210/en.2008-0090
• Publication Date: 2008-10-02T01:35:54Z
• Authors: Yu-Lin Yang; Yi-Shiuan Liu; Lea-Yea Chuang; Jinn-Yuh Guh; Tao-Chen Lee; Tung-Nan Liao; Min-Yuan Hung; Tai-An Chiang
• Keywords: Male; 0301 basic medicine; Receptor, Transforming Growth Factor-beta Type I; Bone Morphogenetic Protein 2; Protein Serine-Threonine Kinases; Kidney; Fibrosis; Rats; 3. Good health; Rats, Sprague-Dawley; Transforming Growth Factor beta1; 03 medical and health sciences; Metabolism; Cytoprotection; Animals; Humans; Kidney Diseases; Rats, Transgenic; Receptors, Transforming Growth Factor beta; Cells, Cultured; Ureteral Obstruction

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.