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BMP-7 and Proximal Tubule Epithelial Cells: Activation of Multiple Signaling Pathways Reveals a Novel Anti-fibrotic Mechanism

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Abstract

Purpose

Bone morphogenic protein-7 (BMP-7) is a member of the transforming growth factor β (TGFβ) superfamily involved in organogenesis. Recent work suggests that BMP-7 can reverse the fibrotic effects of TGFβ but the underlying mechanism is unknown. We sought to determine BMP-7 signaling and its modulation of TGFβ 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 TGFβ-induced p38 MAP activation and the p38-dependent TGFβ-induced Fn secretion by PTECs.

Conclusion

We have shown novel p38/Smad signaling along a BMP-7 gradient and demonstrated BMP-7 regulation of TGFβ MAP kinase signaling and fibrotic outcomes.

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Abbreviations

BMP-7:

Bone morphogenic protein-7

Fn:

Fibronectin

HKC-8:

HKC-clone 8

MAP:

Mitogen activated protein

PTECs:

Proximal tubule epithelial cells

TGFβ:

Transforming growth factor β

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Acknowledgments

South West Thames Kidney Fund supported this work. We thank Mrs Ioana Niculescu-Duvaz and Dr Alex Pearson of the South West Thames Institute For Renal Research, St. Helier Hospital for their technical advice. The HKC-8 cells were the kind gift of Dr. Lorraine Racusen of John Hopkins University, Baltimore.

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Correspondence to Reza Motazed.

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This work was supported by a fellowship grant from the SWT Kidney Fund; RM is the SWT Kidney Fund Research Fellow.

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Motazed, R., Colville-Nash, P., Kwan, J.T.C. et al. BMP-7 and Proximal Tubule Epithelial Cells: Activation of Multiple Signaling Pathways Reveals a Novel Anti-fibrotic Mechanism. Pharm Res 25, 2440–2446 (2008). https://doi.org/10.1007/s11095-008-9551-1

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