title: BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation.
abstract: Adult renal progenitor cells (ARPCs) isolated from the human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling, and regeneration processes in several tissues. The aim of this study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidneys, and it was upregulated in vivo after delayed graft function (DGF) of renal transplantation, a condition of AKI. ARPCs expressed BMP receptors, suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced reactive oxygen species (ROS) production, NADPH oxidase activity, and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2-expressing CD133+ cells at the tubular level after DGF. BMP-2 incubation induced α-smooth muscle actin (SMA), collagen I, and fibronectin protein expression in ARPCs. Moreover, α-SMA colocalized with CD133 in vivo after DGF. The oxidative stimulus (H(2)O(2)) induced α-SMA expression in ARPCs, while the antioxidant N-acetyl-cysteine inhibited BMP-2-induced α-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that 1) ARPCs express BMP-2, 2) this expression is increased in a model of AKI; 3) BMP-2 may induce the commitment of ARPCs toward a myofibroblastic phenotype in vitro and in vivo; and 4) this profibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage.
authors.affiliation: Department of Emergency and Organ Transplantation, University Aldo Moro of Bari, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Simone
authors.forename: Carmela
authors.initials: C
authors.lastname: Cosola
authors.forename: Antonia
authors.initials: A
authors.lastname: Loverre
authors.forename: Marica
authors.initials: M
authors.lastname: Cariello
authors.forename: Fabio
authors.initials: F
authors.lastname: Sallustio
authors.forename: Federica
authors.initials: F
authors.lastname: Rascio
authors.forename: Loreto
authors.initials: L
authors.lastname: Gesualdo
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Schena
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Grandaliano
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pertosa
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism* / Q000473:pathology; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D005353:Fibronectins; D017382:Reactive Oxygen Species; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human