Bone Morphogenetic Protein-7 Signals Opposing Transforming Growth Factor β in Mesangial Cells*
- ‡ To whom correspondence should be addressed: Harbor-UCLA Research and Education Inst., 1124 West Carson St., C-1-A, Torrance, CA 90502. Tel.: 310-222-3891; Fax: 210-782-1837; E-mail: rhirschberg{at}rei.edu.
Abstract
Bone morphogenetic protein-7 (BMP7) is expressed in adult kidney and reduces renal fibrogenesis when given exogenously to rodents with experimental chronic nephropathies. In mesangial cells that regulate glomerular fibrosis in vivo, BMP7 inhibits transforming growth factor β (TGF-β)-driven fibrogenesis, primarily by preventing the TGF-β-dependent down-regulation of matrix degradation and up-regulation of PAI-1. The signals and mechanisms of the BMP7 opposition to actions of TGF-β are unknown. Here we show in mesangial cells that BMP7 reduces nuclear accumulation of Smad3 and blocks the transcriptional up-regulation of the TGF-β/Smad3 target, CAGA-lux. Smad5 knock-down impairs the ability of BMP7 to interfere with the activation of CAGA-lux and the accumulation of PAI-1 by TGF-β indicating that Smad5 is required. Smad5 knock-down also reduces the rise in Smad6 upon BMP7. Forced expression of smad5 (found to be the preferred BMP7-induced receptor-activated Smad signal in mesangial cells) or of smad6 mimics BMP7 in opposing the increase in transcriptional activation of PAI-1 and its secretion upon TGF-β. This suggests a model for the BMP7-induced opposition to TGF-β-dependent mesangial fibrogenesis requiring Smad5; the model involves the inhibitory Smad6 downstream of Smad5 as well as reduced availability of Smad3 in the nucleus. BMP7 does not require signaling through Erk1/2, p38, or JNK and does not utilize the TGF-β transcriptional co-repressors Ski or SnoN in mesangial cells. These studies provide first insights into mechanisms through which BMP7 opposes TGF-β-induced glomerular fibrogenesis.
Footnotes
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↵1 The abbreviations used are: BMP, bone morphogenetic protein; TGF-β, transforming growth factor β; R-Smad, receptor-activated Smad; rhBMP7, recombinant human BMP7; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; MLECs, mink lung epithelial cells; PBS, phosphate-buffered saline; rhTGF-β1, recombinant human TGF-β1; siRNA, small interfering RNA.
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↵* This work was supported by National Institutes of Health Grant DK 63360 and Juvenile Diabetes Research Foundation Grant 1-2004-78. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Received November 3, 2003.
- Revision received March 24, 2004.
- The American Society for Biochemistry and Molecular Biology, Inc.
