Epithelial-mesenchymal transition (EMT) in kidney fibrosis: Fact or fantasy?

Department of Anatomy and Developmental Biology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
The Journal of clinical investigation (Impact Factor: 13.22). 02/2011; 121(2):468-74. DOI: 10.1172/JCI44595
Source: PubMed


Epithelial-mesenchymal transition (EMT) has become widely accepted as a mechanism by which injured renal tubular cells transform into mesenchymal cells that contribute to the development of fibrosis in chronic renal failure. However, an increasing number of studies raise doubts about the existence of this process in vivo. Herein, we review and summarize both sides of this debate, but it is our view that unequivocal evidence supporting EMT as an in vivo process in kidney fibrosis is lacking.

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Available from: Brigitte Kaissling, Oct 09, 2015
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    • "The key feature of renal interstitial fibrosis is the accumulation and deposition of extracellular matrix (ECM), which is thought to be produced mainly by myofibroblasts [2], [3]. Over the past decade, Epithelial-mesenchymal transition (EMT) of tubular epithelial cells, characterized by loss of epithelial cell characteristics, and gain of ECM-producing myofibroblast characteristics, is an important pathway in myofibroblast production and is a key event in the pathogenesis and progression of renal interstitial fibrosis [4], [5], [6]. Recent cell lineage tracking experiments showed that EMT did not contribute to myofibroblast formation in kidney [7], [8]. "
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    ABSTRACT: Obstructive nephropathy is an aggressive form of chronic kidney disease (CKD), which is characterized by an epithelial-to-mesenchymal transition (EMT) and interstitial fibrosis. However, the molecular mechanisms of EMT and fibrosis are complex and not fully understood. In this study, we investigated the contribution of Akt2 to experimental renal EMT and fibrosis using the well-established model of unilateral ureteral obstruction (UUO). We found that Akt2 and phosphor (p)-Akt protein levels were increased in the obstructed kidneys. UUO induced activation of transforming growth factor-β1 (TGF-β1) signaling. Importantly, knockout of Akt2 suppressed UUO-induced EMT, kidney fibrosis, increased GSK3β activity, and decreased expression of Snail and β-catenin. Inhibition of GSK3β with LiCl (the inhibitor of GSK3β) increased the expression of Snail and β-catenin in cultured kidney epithelial cells. Our findings suggest that Akt2 partially contributes to interstitial fibrosis following UUO and that inhibition of this signaling pathway may provide a novel approach of prevent progression of renal fibrosis.
    PLoS ONE 08/2014; 9(8):e105451. DOI:10.1371/journal.pone.0105451 · 3.23 Impact Factor
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    • "Epithelial-to-mesenchymal transition (EMT), a major contributor to the pathogenesis of renal fibrosis, leads fully differentiated epithelial cells to change into matrix-producing myofibroblasts [9]. It is characterized by the loss of epithelial characteristics (E-cadherin) and increased mesenchymal phenotype (alpha smooth muscle actin [α-SMA], Snail, and fibronectin) [10]. "
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) occurs in stressed tubular epithelial cells, contributing to renal fibrosis. Initial mechanisms promoting EMT are unknown. Pressure force is an important mechanism contributing to the induction and progression of renal fibrogenesis in ureteric obstruction. In our study of cultured rat renal tubular cells (NRK-52E) under 60 mmHg of pressure, we found that the epithelial marker E-cadherin decreased and mesenchymal markers, e.g., α-smooth muscle actin, fibronectin and Snail, increased. Pressure also induced the expression of connective tissue growth factor and transforming growth factor-β. MicroRNA array assays showed that pressure reduced miR-328 at the initial stage of pressurization. We identified a potential target sequence of miR-328 in rat CD44 3'-untranslated regions. In contrast with the miR-328 expression, CD44 expression was up-regulated at the initial pressurization stage. We also found that miR-328 expression decreased and CD44 increased in ureteric obstruction kidneys in the animal study. CD44 siRNA transfection significantly increased E-cadherin expression and inhibited pressure-induced EMT. Both hyaluronan binding peptide pep-1 and osteopontin neutralizing antibody inhibited pressure-induced EMT. Our results suggest that miR-328-mediated CD44 transient upregulation is an important trigger of the pressure-induced EMT in renal fibrosis.
    PLoS ONE 06/2014; 9(6):e99802. DOI:10.1371/journal.pone.0099802 · 3.23 Impact Factor
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    • "REVIEW Disease Models & Mechanisms (2014) doi:10.1242/dmm.012062 Box 1. EMT and αSMA: conflicting models Although studies in various organs of animal models have suggested that fibrogenic myofibroblasts can derive from epithelial cells that undergo epithelial-to-mesenchymal transition (EMT) and migrate into the interstitial compartment (Iwano et al., 2002; Kim et al., 2006; LeBleu et al., 2013; Rowe et al., 2011), these findings have been questioned by compelling lineage-tracing studies and other means (Chu et al., 2011; Duffield et al., 2005; Hung et al., 2013; Kriz et al., 2011; Lin et al., 2008; Rock et al., 2011). It is our opinion that the prevailing data indicate that fibrogenic myofibroblasts in lung, kidney and liver arise from resident interstitial cells (i.e. "
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    ABSTRACT: Fibrosis - a debilitating condition that can occur in most organs - is characterized by excess deposition of a collagen-rich extracellular matrix (ECM). At first sight, the activities of proteinases that can degrade matrix, such as matrix metalloproteinases (MMPs), might be expected to be under-expressed in fibrosis or, if present, could function to resolve the excess matrix. However, as we review here, some MMPs are indeed anti-fibrotic, whereas others can have pro-fibrotic functions. MMPs modulate a range of biological processes, especially processes related to immunity and tissue repair and/or remodeling. Although we do not yet know precisely how MMPs function during fibrosis - that is, the protein substrate or substrates that an individual MMP acts on to effect a specific process - experiments in mouse models demonstrate that MMP-dependent functions during fibrosis are not limited to effects on ECM turnover. Rather, data from diverse models indicate that these proteinases influence cellular activities as varied as proliferation and survival, gene expression, and multiple aspects of inflammation that, in turn, impact outcomes related to fibrosis.
    Disease Models and Mechanisms 02/2014; 7(2):193-203. DOI:10.1242/dmm.012062 · 4.97 Impact Factor
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