| First Author | Higgins DF | Year | 2017 |
| Journal | Biochim Biophys Acta | Volume | 1863 |
| Issue | 12 | Pages | 3095-3104 |
| PubMed ID | 28923783 | Mgi Jnum | J:255444 |
| Mgi Id | MGI:6105346 | Doi | 10.1016/j.bbadis.2017.09.011 |
| Citation | Higgins DF, et al. (2017) BMP7-induced-Pten inhibits Akt and prevents renal fibrosis. Biochim Biophys Acta 1863(12):3095-3104 |
| abstractText | Bone morphogenetic protein-7 (BMP-7) counteracts pro-fibrotic effects of TGFbeta1 in cultured renal cells and protects from fibrosis in acute and chronic renal injury models. Using the unilateral ureteral obstruction (UUO) model of chronic renal fibrosis, we investigated the effect of exogenous-rhBMP-7 on pro-fibrotic signaling pathways mediated by TGFbeta1 and hypoxia. Mice undergoing UUO were treated with vehicle or rhBMP-7 (300mug/kg i.p.) every other day for eight days and kidneys analysed for markers of fibrosis and SMAD, MAPK, and PI3K signaling. In the kidney, collecting duct and tubular epithelial cells respond to BMP-7 via activation of SMAD1/5/8. Phosphorylation of SMAD1/5/8 was reduced in UUO kidneys from vehicle-treated animals yet maintained in UUO kidneys from BMP-7-treated animals, confirming renal bioactivity of exogenous rhBMP-7. BMP-7 inhibited Collagen Ialpha1 and Collagen IIIalpha1 gene expression and Collagen I protein accumulation, while increasing expression of Collagen IValpha1 in UUO kidneys. Activation of SMAD2, SMAD3, ERK, p38 and PI3K/Akt signaling occurred during fibrogenesis and BMP-7 significantly attenuated SMAD3 and Akt signaling in vivo. Analysis of renal collecting duct (mIMCD) and tubular epithelial (HK-2) cells stimulated with TGFbeta1 or hypoxia (1% oxygen) to activate Akt provided further evidence that BMP-7 specifically inhibited PI3K/Akt signaling. PTEN is a negative regulator of PI3K and BMP-7 increased PTEN expression in vivo and in vitro. These data demonstrate an important mechanism by which BMP-7 orchestrates renal protection through Akt inhibition and highlights Akt inhibitors as anti-fibrotic therapeutics. |
