TGF-β induced epithelial-mesenchymal transition and the related therapeutic strategy
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Renal interstitial fibrosis(RIF) represents the final common pathology pathway of most forms of kidney disease.Epithelial-mesenchymal transition(EMT) of tubuloepithelial cells plays an important role in RIF.Although a number of factors may initiate EMT in the kidney,the most potent factor is transforming growth factor-β(TGF-β).That the molecular pathways for TGF-β induced EMT have critical relation with the mechanism of RIF.Such represent a potential therapeutic approach,offering a mechanism to slow or even redress established renal interstitial fibrosis.Keywords:
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Matrix metalloproteinases(MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial–mesenchymal transition(EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition(Endo MT) and pericyte-myofibroblast transdifferentiation. Interstitial macrophage infiltration has also been shown to correlate with the severity of kidney fibrosis in various chronic kidney diseases. MMPs secreted by macrophages, especially MMP-9, hasbeen shown by us to be profibrotic by induction of tubular cells EMT. EMT is mainly induced by transforming growth factor-β(TGF-β). However, MMP-9 was found by us and others to be up-regulated by TGF-β1 in kidney tubular epithelial cells and secreted by activated macrophages, resulting in EMT and ultimately kidney fibrosis. Therefore, MMP-9 may serve as a potential therapeutic target to prevent kidney fibrosis in chronic kidney disease. This review, by a particular focus on EMT, seeks to provide a comprehensive understanding of MMPs, especially MMP-9, in kidney fibrosis.
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Interstitial fibrosis, resulting in renal tissue destruction and progressive impairment of organ function, is a hallmark of end-stage kidney disease [1]. The primary sources of matrix synthesis during renal fibrogenesis are activated fibroblasts or myofibroblasts. While their origin remains uncertain, this cell type-predictor of disease progression likely derives largely from resident fibroblasts and epithelial-to-mesenchymal transdifferentiated (EMT) tubular epithelial cells [2]. The transforming growth factor-β (TGF-β)/SMAD system is a potent, perhaps the most well-characterized, inducer of myofibroblast differentiation and EMT. TGF-β drives EMT in renal epithelial cells and promotes fibrosis in animal models by engaging effector pathways and their downstream target genes that impact both the inflammatory and scarring stages of the injury response [3]. SMAD-mediated signaling initiated by TGF-β is pivotal for induction of EMT, fibroblast activation and renal fibrosis [2,3]. SMAD3, in particular, appears critical in several in vivo models of renal fibrosis. This was, indeed, confirmed by the finding that SMAD3-deficient mice are significantly protected from disease progression. TGF-β also activates non-SMAD-dependent pathways [4] that impact the expression of pro-fibrotic genes. The continued characterization of such highly-interactive transduction events initiated by TGF-β/TGF-β receptor interactions will likely lead to identification of novel opportunities for anti-fibrotic therapy.
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Pathogenesis
Myofibroblast
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Renal interstitial fibrosis represents the final common pathway of all chronic disease.The mechanism of renal interstitial fibrosis is very complex.It is not entirely clear now.The study found that epithelial-to-mesenchymal transition plays an important role in the renal interstitial fibrosis.Inhibition of epithelial-to-mesenchymal transition may help to slow down the development and progression of renal interstitial fibrosis.The article mainly reviews the mechanism and treatment of epithelial-to-mesenchymal transition.
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Epithelial-to-mesenchymal transition; Renal interstitial fibrosis; drug therapy
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Epithelial-mesenchymal transition (EMT) is described as the process in which injured renal tubular epithelial cells undergo a phenotype change, acquiring mesenchymal characteristics and morphing into fibroblasts. Initially, it was widely thought of as a critical mechanism of fibrogenesis underlying chronic kidney disease. However, evidence that renal tubular epithelial cells can cross the basement membrane and become fibroblasts in the renal interstitium is rare, leading to debate about the existence of EMT. Recent research has demonstrated that after injury, renal tubular epithelial cells acquire mesenchymal characteristics and the ability to produce a variety of profibrotic factors and cytokines, but remain attached to the basement membrane. On this basis, a new concept of "partial epithelial-mesenchymal transition (pEMT)" was proposed to explain the contribution of renal epithelial cells to renal fibrogenesis. In this review, we discuss the concept of pEMT and the most recent findings related to this process, including cell cycle arrest, metabolic alternation of epithelial cells, infiltration of immune cells, epigenetic regulation as well as the novel signaling pathways that mediate this disturbed epithelial-mesenchymal communication. A deeper understanding of the role and the mechanism of pEMT may help in developing novel therapies to prevent and halt fibrosis in kidney disease.
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Liver fibrosis is a gradual process of increased secretion and decreased degradation of extra-cellular materials. Two cell types are now well recognized as being involved in liver fibrosis, i.e. hepatic stellate cells (HSCs) and portal mesenchymal cells. T iis process is initiated by the damage of hepatic cells, which leads to activation of hepatic stellate cells that differentiate into myofibroblasts leading to the formation of liver fibrosis. On the other hand, the epithelial-mesenchymal transition and mesenchymal-epithelial transition are crucial for the regulation of cellular plasticity during liver fibrosis. The EMT is a process in which molecular reprogramming leads epithelial cells to adopt a mesenchymal phenotype. During EMT, epithelial cells gain mesenchymal features which include changes in the expression of epithelial markers. The EMT process plays fundamental roles during embryogenesis, tissue fibrosis, and carcinogenesis. As multiple experimental studies of liver fibrosis have confirmed that established liver fibrosis is reversible upon cessation of the causative agent, modulation of the EMT markers could be promising as potential therapeutic agents. Better understanding of the molecular cascades of intracellular fibrogenic signaling and genetic factors that controlling the expression of EMT markers would be a powerful strategy for early diagnosis and treatment liver fibrosis at the genetic level. Activating or silencing of the responsible genes may be an efficient and more specific approach for treating liver fibrosis either through the arrest of EMT or the induction of MET.
Hepatic stellate cell
Hepatic fibrosis
Reprogramming
Myofibroblast
Transdifferentiation
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Epithelial-mesenchymal transition (EMT) plays an important role in embryogenesis and organ formation. Over the last 10–15 years it has been established that EMT is a significant mechanism of tumor progression and metastasis formation and also of progressive tissue fibrosis in the kidney, liver and lung. EMT seen in these diverse physiological and pathophysiological contexts shares a number of stages and modules, but also carries distinct, context specific characteristics. EMT in tissue fibrosis is a form of reverse embryogenesis, when highly specialized epithelial cells in the specific organs will respond to injury with loosing their epithelial characteristics and functions and regaining characteristics of the cells from which they originated. EMT in the context of tissue fibrosis can be induced by different forms of injury or a set of humoral factors. The process is regulated by a complex balance of humoral and microenvironmental stimuli, in which cell-cell contacts and interaction of the transitioning cell with the extracellular matrix components is very important. Intense research in this exciting field yielded good understanding of many of the details of this fascinating process, although numerous questions still await proper answers. There is indication that understanding of the molecular mechanisms underlying “fibrotic” EMT may lead to the design of specific and effective therapeutic measures for progressive tissue fibrosis.
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Epithelial-to-mesenchymal transition refers to the process by which epithelial cells lose typical characteristics and acquire mesenchymal traits.The transition of alveolar epithelial cells to mesenchymal cells is an important source of myofibroblasts.Pulmonary fibrosis is characterized by proliferation of myofibroblasts and deposition of extracellular matrix,and is a common result of various interstitial lung diseases.Transforming growth factor-β,the strongest factor inducing fibrosis,mediates a number of signal pathways involved in fibrosis.Therefore,it is significant to study the role of epithelialto-mesenchymal transition and signal pathways in pulmonary fibrosis.
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Epithelial-to-mesenchymal transition; Pulmonary interstitial fibrosis; Signal pathways
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Epithelial-to-mesenchymal cell transformation (EMT) is the trans-differentiation of tubular epithelial cells into myofibroblasts, an event underlying progressive chronic kidney disease in diabetes, resulting in fibrosis. Mainly reported in proximal regions of the kidney, EMT is now recognized as a key contributor to the loss of renal function throughout the nephron in diabetic nephropathy (DN). Concomitant upregulation of TGF-beta in diabetes makes this pro-fibrotic cytokine an obvious candidate in the development of these fibrotic complications. This article reviews recent findings clarifying our understanding of the role of TGF-beta and associated sub-cellular proteins in EMT.To understand the pathology of EMT and the role of TGF-beta, we reviewed the literature using PubMed for English language articles that contained key words related to EMT, TGF-beta and DN.EMT and phenotypic plasticity of epithelial cells throughout the nephron involves cytoskeletal reorganization and de novo acquisition of classic mesenchymal markers. Concurrent downregulation of epithelial adhesion molecules results in a loss of function and decreased cell coupling, contributing to a loss of epithelial integrity. TGF-beta1 is pivotal in mediating these phenotypic changes.TGF-beta-induced EMT is a key contributor to fibrotic scar formation as seen in DN, and novel routes for future therapeutic intervention are discussed.
Myofibroblast
Transdifferentiation
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Fibrosis is often involved in the pathogenesis of various chronic progressive diseases such as interstitial pulmonary disease. Pathological hallmark is the formation of fibroblastic foci, which is associated with the disease severity. Mesenchymal cells consisting of the fibroblastic foci are proposed to be derived from several cell sources, including originally resident intrapulmonary fibroblasts and circulating fibrocytes from bone marrow. Recently, mesenchymal cells that underwent epithelial-mesenchymal transition (EMT) have been also supposed to contribute to the pathogenesis of fibrosis. In addition, EMT can be induced by transforming growth factor β, and EMT can be enhanced by pro-inflammatory cytokines like tumor necrosis factor α. The gel contraction assay is an ideal in vitro model for the evaluation of contractility, which is one of the characteristic functions of fibroblasts and contributes to wound repair and fibrosis. Here, the development of a gel contraction assay is demonstrated for evaluating contractile ability of mesenchymal cells that underwent EMT.
Fibrocyte
Pathogenesis
Mesenchyme
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