title: Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition.
abstract: Human cytomegalovirus (HCMV) infection is associated epidemiologically with poor outcome of renal allografts due to mechanisms which remain largely undefined. Transforming growth factor-β1 (TGF-β1), a potent fibrogenic cytokine, is more abundant in rejecting renal allografts that are infected with either HCMV or rat CMV as compared to uninfected, rejecting grafts. TGF-β1 induces renal fibrosis via epithelial-to-mesenchymal transition (EMT) of renal epithelial cells, a process by which epithelial cells acquire mesenchymal characteristics and a migratory phenotype, and secrete molecules associated with extracellular matrix deposition and remodeling. We report that human renal tubular epithelial cells infected in vitro with HCMV and exposed to TGF-β1 underwent morphologic and transcriptional changes of EMT, similar to uninfected cells. HCMV infected cells after EMT also activated extracellular latent TGF-β1 via induction of MMP-2. Renal epithelial cells transiently transfected with only the HCMV IE1 or IE2 open reading frames and stimulated to undergo EMT also induced TGF-β1 activation associated with MMP-2 production, suggesting a role for these viral gene products in MMP-2 production. Consistent with the function of these immediate early gene products, the antiviral agents ganciclovir and foscarnet did not inhibit TGF-β1 production after EMT by HCMV infected cells. These results indicate that HCMV infected renal tubular epithelial cells can undergo EMT after exposure to TGF-β1, similar to uninfected renal epithelial cells, but that HCMV infection by inducing active TGF-β1 may potentiate renal fibrosis. Our findings provide in vitro evidence for a pathogenic mechanism that could explain the clinical association between HCMV infection, TGF-β1, and adverse renal allograft outcome.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. mshimamura@peds.uab.edu
authors.forename: Masako
authors.initials: M
authors.lastname: Shimamura
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Murphy-Ullrich
authors.forename: William J
authors.initials: WJ
authors.lastname: Britt
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000472:pathogenicity*; D003586:Cytomegalovirus Infections / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D058750:Epithelial-Mesenchymal Transition; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism* / Q000821:virology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1