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 α-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-β1 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. E-mail: liuy@upmc.edu.

Epithelial-mesenchymal transition (EMT), a process by which differentiated epithelial cells undergo a phenotypic conversion that gives rise to the matrix-producing fibroblasts and myofibroblasts, is increasingly recognized as an integral part of tissue fibrogenesis after injury. However, the degree to which this process contributes to kidney fibrosis remains a matter of intense debate and is likely to be context-dependent. EMT is often preceded by and closely associated with chronic interstitial inflammation and could be an adaptive response of epithelial cells to a hostile or changing microenvironment. In addition to tubular epithelial cells, recent studies indicate that endothelial cells and glomerular podocytes may also undergo transition after injury. Phenotypic alteration of podocytes sets them in motion to functional impairment, resulting in proteinuria and glomerulosclerosis. Several intracellular signal transduction pathways such as TGFβ/Smad, integrin-linked kinase (ILK) and Wnt/β-catenin signaling are essential in controlling the process of EMT and presently are potential targets of antifibrotic therapy. This review highlights the current understanding of EMT and its underlying mechanisms to stimulate further discussion on its role, not only in the pathogenesis of renal interstitial fibrosis but also in the onset of podocyte dysfunction, proteinuria, and glomerulosclerosis.

Wnts compose a family of signaling proteins that play an essential role in kidney development, but their expression in adult kidney is thought to be silenced. Here, we analyzed the expression and regulation of Wnts and their receptors and antagonists in normal and fibrotic kidneys after obstructive injury. In the normal mouse kidney, the vast majority of 19 different Wnts and 10 frizzled receptor genes was expressed at various levels. After unilateral ureteral obstruction, all members of the Wnt family except Wnt5b, Wnt8b, and Wnt9b were upregulated in the fibrotic kidney with distinct dynamics. In addition, the expression of most Fzd receptors and Wnt antagonists was also induced. Obstructive injury led to a dramatic accumulation of β-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/β-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal β-catenin abundance. Delivery of the Wnt antagonist Dickkopf-1 gene significantly reduced renal β-catenin accumulation and inhibited the expression of Wnt/β-catenin target genes. Furthermore, gene therapy with Dickkopf-1 inhibited myofibroblast activation; suppressed expression of fibroblast-specific protein 1, type I collagen, and fibronectin; and reduced total collagen content in the model of obstructive nephropathy. In summary, these results establish a role for Wnt/β-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target.