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,
    • "Nowadays, the contribution of EMT in myofibroblast presence during kidney fibrosis is uncertain. Some relative early studies suggested that most myofibroblasts are produced by EMT of endothelial or epithelial cells (Kalluri & Neilson, 2003) whereas most recent studies reveals that the contribution of EMT as a source of myofibroblasts is very low (Kriz et al., 2011). A very recent study suggests an alternative that make these two facts compatible: myofibroblasts do not come primarily from endothelial or epithelial cells after suffering EMT, but partial and reversible epithelial EMT is necessary for myofibroblast appearance and activation, and thus, for renal fibrosis (Grande et al., 2015). "
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    ABSTRACT: The understanding of renal fibrosis in chronic kidney disease (CKD) remains as a challenge. More than 10% of the population of developed countries suffer from CKD. Proliferation and activation of myofibroblasts and accumulation of extracellular matrix proteins are the main features of kidney fibrosis, a process in which a large number of cytokines are involved. Targeting cytokines responsible for kidney fibrosis development might be an important strategy to face the problem of CKD. The increasing knowledge of the signaling pathway network of the transforming growth factor beta (TGF-β) superfamily members, such as the profibrotic cytokine TGF-β1 or the bone morphogenetic proteins (BMPs), and their involvement in the regulation of kidney fibrosis, has stimulated numerous research teams to look for potential strategies to inhibit profibrotic cytokines or to enhance the anti-fibrotic actions of other cytokines. The consequence of all these studies is a better understanding of all these canonical (Smad-mediated) and non-canonical signaling pathways. In addition, the different receptors involved for signalling of each cytokine, the different combinations of type I-type II receptors, and the presence and function of co-receptors that can influence the biological response have been also described. However, are these studies leas to suitable strategies to block the appearance and progression of kidney fibrosis? In this review, we offer a critical perspective analyzing the achievements using the most important strategies developed up till now: TGF-β antibodies, chemical inhibitors of TGF-β receptors, miRNAs and signaling pathways and BMP agonists with a potential role as therapeutic molecules against kidney fibrosis.
    Pharmacology [?] Therapeutics 10/2015; DOI:10.1016/j.pharmthera.2015.10.003 · 9.72 Impact Factor
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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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