Epithelial to mesenchymal transition in renal fibrogenesis: pathologic significance, molecular mechanism, and therapeutic intervention.
Mature tubular epithelial cells in adult kidney can undergo epithelial-to-mesenchymal transition (EMT), a phenotypic conversion that is fundamentally linked to the pathogenesis of renal interstitial fibrosis. Emerging evidence indicates that a large proportion of interstitial fibroblasts are actually originated from tubular epithelial cells via EMT in diseased kidney. Moreover, selective blockade of EMT in a mouse genetic model dramatically reduces fibrotic lesions after obstructive injury, underscoring a definite importance of EMT in renal fibrogenesis. Tubular EMT is proposed as an orchestrated, highly regulated process that consists of four key steps: (1) loss of epithelial cell adhesion; (2) de novo alpha-smooth muscle actin expression and actin reorganization; (3) disruption of tubular basement membrane; and (4) enhanced cell migration and invasion. Of the many factors that regulate EMT in different ways, transforming growth factor-beta1 is the most potent inducer that is capable of initiating and completing the entire EMT course, whereas hepatocyte growth factor and bone morphogenetic protein-7 act as EMT inhibitors both in vitro and in vivo. Multiple intracellular signaling pathways have been implicated in mediating EMT, in which Smad/integrin-linked kinase may play a central role. This article attempts to provide a comprehensive review of recent advances on understanding the pathologic significance, molecular mechanism, and therapeutic intervention of EMT in the setting of chronic renal fibrosis.
Liu
Youhua
Y
Division of Cellular and Molecular Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. liuy@upmc.edu
D000818:Animals; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008648:Mesoderm / Q000166:cytology / Q000473:pathology / Q000502:physiology; D015398:Signal Transduction; D019459:Urothelium / Q000473:pathology