BMP7-induced-Pten inhibits Akt and prevents renal fibrosis

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Title: BMP7-induced-Pten inhibits Akt and prevents renal fibrosis
Authors: Higgins, Debra F.
Weart, Leah
Masterson, Enda
Tennant, Sadhbh
Grebnev, Gleb
Martin, Finian
Godson, Catherine
et al.
Permanent link: http://hdl.handle.net/10197/9296
Date: 18-Sep-2017
Abstract: 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 (300 μg/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
Funding Details: Health Research Board
Science Foundation Ireland
Type of material: Journal Article
Publisher: Elsevier
Copyright (published version): 2017 Elsevier
Keywords: Fibrosis;Anti-fibrotic;PTEN;Akt;TGFβ1;Hypoxia
DOI: 10.1016/j.bbadis.2017.09.011
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
Medicine Research Collection

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