Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition.
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 e...
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2010-11-01
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doaj-692632b504b946ae9ae22b0cddb52c262020-11-25T01:15:21ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742010-11-01611e100117010.1371/journal.ppat.1001170Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition.Masako ShimamuraJoanne E Murphy-UllrichWilliam J BrittHuman 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.http://europepmc.org/articles/PMC2973835?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Masako Shimamura Joanne E Murphy-Ullrich William J Britt |
spellingShingle |
Masako Shimamura Joanne E Murphy-Ullrich William J Britt Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition. PLoS Pathogens |
author_facet |
Masako Shimamura Joanne E Murphy-Ullrich William J Britt |
author_sort |
Masako Shimamura |
title |
Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition. |
title_short |
Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition. |
title_full |
Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition. |
title_fullStr |
Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition. |
title_full_unstemmed |
Human cytomegalovirus induces TGF-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition. |
title_sort |
human cytomegalovirus induces tgf-β1 activation in renal tubular epithelial cells after epithelial-to-mesenchymal transition. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Pathogens |
issn |
1553-7366 1553-7374 |
publishDate |
2010-11-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC2973835?pdf=render |
work_keys_str_mv |
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