BMP7-induced-Pten inhibits Akt and prevents renal fibrosis

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2017-12, Vol.1863 (12), p.3095-3104
• Main Authors: Higgins, Debra F., Ewart, Leah M., Masterson, Enda, Tennant, Sadhbh, Grebnev, Gleb, Prunotto, Marco, Pomposiello, Sylvia, Conde-Knape, Karin, Martin, Finian M., Godson, Catherine
• Format: Article
• Language: English
• Subjects: Akt; Animals; Anti-fibrotic; Bone Morphogenetic Protein 7 - metabolism; Bone Morphogenetic Protein 7 - pharmacology; Cell Hypoxia - physiology; Cell Line; Collagen - metabolism; Disease Models, Animal; Fibrosis; Fibrosis - enzymology; Fibrosis - pathology; Fibrosis - prevention & control; Hypoxia; Kidney Diseases - enzymology; Kidney Diseases - pathology; Kidney Diseases - prevention & control; Kidney Tubules - drug effects; Kidney Tubules - pathology; Mice; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; PTEN; PTEN Phosphohydrolase - biosynthesis; PTEN Phosphohydrolase - metabolism; Signal Transduction - drug effects; Smad Proteins - metabolism; TGFβ1; Transforming Growth Factor beta1 - metabolism; Up-Regulation
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2017.09.011

Bone morphogenetic protein-7 (BMP-7) counteracts pro-fibrotic effects of TGFβ1 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 TGFβ1 and hypoxia. Mice undergoing UUO were treated with vehicle or rhBMP-7 (300μg/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 Iα1 and Collagen IIIα1 gene expression and Collagen I protein accumulation, while increasing expression of Collagen IVα1 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 TGFβ1 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. •BMP-7 inhibits PI3K/Akt in UUO-induced fibrosis, and in tubular and collecting duct cells but not in renal fibroblasts.•BMP-7 inhibits SMAD3 and promotes SMAD2 phosphorylation in fibrotic renal tissue and renal epithelial cell lines in vitro.•BMP-7 reduced Collagen I and III expression while promoting Collagen IV expression in kidney tissue in vivo.•BMP-7 did not alter myofibroblast activation or α-SMA expression during UUO-induced renal fibrosis in vivo.•BMP-7 up-regulated PTEN expression, causing inhibition of PI3K/Akt in vivo and in vitro.