BMP-7 and proximal tubule epithelial cells: activation of multiple signaling pathways reveals a novel anti-fibrotic mechanism.
OBJECTIVE
Bone morphogenic protein-7 (BMP-7) is a member of the transforming growth factor beta (TGFbeta) superfamily involved in organogenesis. Recent work suggests that BMP-7 can reverse the fibrotic effects of TGFbeta but the underlying mechanism is unknown. We sought to determine BMP-7 signaling and its modulation of TGFbeta induced fibrotic outcomes in adult human proximal tubule epithelial cells (PTECs).


METHODS
The effect of BMP-7 on phospho-p38 was assessed by Western blotting, p38 ELISA and Bio-plex phospho-protein assay. Secreted fibronectin (Fn) was measured by ELISA.


RESULTS
BMP-7 had a concentration-dependent effect on intracellular signaling activating Smad 1/5/8 at higher concentrations and p38 mitogen activated protein (MAP) kinase at lower concentrations in both primary and transformed PTECs; BMP-7 caused phosphorylation of p38 at 2.5 ng/ml and Smads at 200 ng/ml. Similarly, nuclear accumulation of phospho-p38 and Smad were observed at these respective concentrations. These results suggested an inverse relationship between activation of Smads and p38 MAP kinase in this context. Consistent, with this BMP7 at 200 ng/ml reduced TGFbeta-induced p38 MAP activation and the p38-dependent TGFbeta-induced Fn secretion by PTECs.


CONCLUSIONS
We have shown novel p38/Smad signaling along a BMP-7 gradient and demonstrated BMP-7 regulation of TGFbeta MAP kinase signaling and fibrotic outcomes.
Motazed
Reza
R
South West Thames Institute For Renal Research, Epsom and St Helier University, NHS Trust, Wrythe Lane, Carshlaton, Surrey, SM5 1AA, UK. Reza.motazed@epsom-sthelier.nhs.uk
Colville-Nash
Paul
P
Kwan
Jonathan T C
JT
Dockrell
Mark E C
ME
D021581:Active Transport, Cell Nucleus; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism* / Q000494:pharmacology; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D005353:Fibronectins; D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases