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 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-b1 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-b1 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. © 2010 shimamura et al.