BMP-7 and proximal tubule epithelial cells: Activation of multiple signaling pathways reveals a novel anti-fibrotic mechanism

Purpose. Bone morphogenic protein-7 (BMP-7) is a member of the transforming growth factor beta (TGF beta) superfamily involved in organogenesis. Recent work suggests that BMP-7 can reverse the fibrotic effects of TGF beta but the underlying mechanism is unknown. We sought to determine BMP-7 signaling and its modulation of TGF beta 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 TGF beta-induced p38 MAP activation and the p38-dependent TGF beta-induced Fn secretion by PTECs. Conclusions. We have shown novel p38/Smad signaling along a BMP-7 gradient and demonstrated BMP-7 regulation of TGF beta MAP kinase signaling and fibrotic outcomes.