scholarly journals Emerging Therapeutic Strategies for Attenuating Tubular EMT and Kidney Fibrosis by Targeting Wnt/β-Catenin Signaling

2022 ◽  
Vol 12 ◽  
Author(s):  
Lichao Hu ◽  
Mengyuan Ding ◽  
Weichun He
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tissue Injury ◽  
Therapeutic Strategies ◽  
Potential Therapeutic Target ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Genes Expression ◽  
Phenotypic Transformation ◽  
Clinical Prevention

Epithelial-mesenchymal transition (EMT) is defined as a process in which differentiated epithelial cells undergo phenotypic transformation into myofibroblasts capable of producing extracellular matrix, and is generally regarded as an integral part of fibrogenesis after tissue injury. Although there is evidence that the complete EMT of tubular epithelial cells (TECs) is not a major contributor to interstitial myofibroblasts in kidney fibrosis, the partial EMT, a status that damaged TECs remain inside tubules, and co-express both epithelial and mesenchymal markers, has been demonstrated to be a crucial stage for intensifying fibrogenesis in the interstitium. The process of tubular EMT is governed by multiple intracellular pathways, among which Wnt/β-catenin signaling is considered to be essential mainly because it controls the transcriptome associated with EMT, making it a potential therapeutic target against kidney fibrosis. A growing body of data suggest that reducing the hyperactivity of Wnt/β-catenin by natural compounds, specific inhibitors, or manipulation of genes expression attenuates tubular EMT, and interstitial fibrogenesis in the TECs cultured under profibrotic environments and in animal models of kidney fibrosis. These emerging therapeutic strategies in basic researches may provide beneficial ideas for clinical prevention and treatment of chronic kidney disease.

scholarly journals Neutrophil extracellular traps induce the epithelial-mesenchymal transition: implications in post-COVID-19 fibrosis

2020 ◽  
Author(s):  
Laura Pandolfi ◽  
Sara Bozzini ◽  
Vanessa Frangipane ◽  
Elena Percivalle ◽  
Ada De Luigi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tissue Injury ◽  
Neutrophil Extracellular Traps ◽  
Lung Epithelial Cells ◽  
Epithelial Cell Line ◽  
High Concentration ◽  
Mesenchymal Transition ◽  
Extracellular Traps ◽  
Lung Epithelial

AbstractThe release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19.Neutrophils activated with PMA (PMA-Neu), a stimulus known to induce NETs formation, induce both EMT and cell death in the lung epithelial cell line, A549. Notably, NETs isolated from PMA-Neu induce EMT without cell damage. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs. Thus, we tested in an in vitro alveolar model the hypothesis that virus-induced NET may drive EMT. Co-culturing A549 at air-liquid interface with alveolar macrophages, neutrophils and SARS-CoV2, we demonstrated a significant induction of the EMT in A549 together with high concentration of NETs, IL8 and IL1β, best-known inducers of NETosis. Lung tissues of COVID-19 deceased patients showed that epithelial cells are characterized by increased mesenchymal markers. These results show for the first time that NETosis plays a major role in triggering lung fibrosis in COVID-19 patients.

scholarly journals The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis

2020 ◽  
Vol 134 (21) ◽  
pp. 2873-2891
Author(s):  
Sarah W.Y. Lok ◽  
Wai Han Yiu ◽  
Hongyu Li ◽  
Rui Xue ◽  
Yixin Zou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Tubules ◽  
Tubular Epithelial Cells ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition

Abstract Protease-activated receptor (PAR)-1 has emerged as a key profibrotic player in various organs including kidney. PAR-1 activation leads to deposition of extracellular matrix (ECM) proteins in the tubulointerstitium and induction of epithelial–mesenchymal transition (EMT) during renal fibrosis. We tested the anti-fibrotic potential of vorapaxar, a clinically approved PAR-1 antagonist for cardiovascular protection, in an experimental kidney fibrosis model of unilateral ureteral obstruction (UUO) and an AKI-to-chronic kidney disease (CKD) transition model of unilateral ischemia–reperfusion injury (UIRI), and dissected the underlying renoprotective mechanisms using rat tubular epithelial cells. PAR-1 is activated mostly in the renal tubules in both the UUO and UIRI models of renal fibrosis. Vorapaxar significantly reduced kidney injury and ameliorated morphologic changes in both models. Amelioration of kidney fibrosis was evident from down-regulation of fibronectin (Fn), collagen and α-smooth muscle actin (αSMA) in the injured kidney. Mechanistically, inhibition of PAR-1 inhibited MAPK ERK1/2 and transforming growth factor-β (TGF-β)-mediated Smad signaling, and suppressed oxidative stress, overexpression of pro-inflammatory cytokines and macrophage infiltration into the kidney. These beneficial effects were recapitulated in cultured tubular epithelial cells in which vorapaxar ameliorated thrombin- and hypoxia-induced TGF-β expression and ECM accumulation. In addition, vorapaxar mitigated capillary loss and the expression of adhesion molecules on the vascular endothelium during AKI-to-CKD transition. The PAR-1 antagonist vorapaxar protects against kidney fibrosis during UUO and UIRI. Its efficacy in human CKD in addition to CV protection warrants further investigation.

scholarly journals Different macrophages equally induce EMT in endometria of adenomyosis and normal

Reproduction ◽  
2017 ◽  
Vol 154 (1) ◽  
pp. 79-92 ◽  
Author(s):  
Min An ◽  
Dong Li ◽  
Ming Yuan ◽  
Qiuju Li ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Quantitative Polymerase Chain Reaction ◽  
Immunohistochemical Analysis ◽  
Secretory Phase ◽  
Normal Endometrium ◽  
Mesenchymal Transition ◽  
Expression Levels ◽  
Endometrial Cells

Endometrial cells and microenvironment are two important factors in the pathogenesis of adenomyosis. Our previous study demonstrated that macrophages can induce eutopic epithelial cells of adenomyosis to suffer from epithelial–mesenchymal transition (EMT). The aim of this study is to detect whether macrophages interacting with epithelial cells equally induce the EMT process in normal and eutopic endometria of healthy and adenomyotic patients; and whether macrophages parallelly polarize to M2. We investigated the expression levels of epithelial cadherin (E-cadherin), neural cadherin (N-cadherin), cytokeratin7 (CK7), vimentin, transforming growth factor-β1 (TGFB1), SMAD3 and pSMAD3 using immunohistochemistry and western blot, and then estimated the genetic levels of CD163, IL10 and MMP12 using real-time quantitative polymerase chain reaction (RT-PCR) in macrophages. Eutopic and normal endometrial tissues were obtained from 20 patients with adenomyosis and 11 control patients without adenomyosis, respectively. The immunohistochemical analysis shows distinct EMT in eutopic endometria in secretory phase; the expression levels of TGFB1, SMAD3 and pSMAD3 that indicate signal pathway of EMT were also higher in secretory phase. Macrophages can induce EMT process in primary endometrial epithelial cells derived from normal and eutopic endometria. After co-culturing, THP-1-derived macrophages polarized to M2. Compared with the eutopic endometrium group, further polarization to M2 was observed in the normal endometrium group. These results indicate that adenomyosis may be promoted by the pathologic EMT of epithelial cells, which is induced by macrophages that incapably polarize to M2.

scholarly journals Cbl-transforming Variants Trigger a Cascade of Molecular Alterations That Lead to Epithelial Mesenchymal Conversion

2000 ◽  
Vol 11 (10) ◽  
pp. 3397-3410 ◽  
Author(s):  
Tanya M. Fournier ◽  
Louie Lamorte ◽  
Christiane R. Maroun ◽  
Mark Lupher ◽  
Hamid Band ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Hepatocyte Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Cell Spreading ◽  
Mesenchymal Transition ◽  
Amino Terminal ◽  
Src Homology ◽  
Hepatocyte Growth

Dispersal of epithelial cells is an important aspect of tumorigenesis, and invasion. Factors such as hepatocyte growth factor induce the breakdown of cell junctions and promote cell spreading and the dispersal of colonies of epithelial cells, providing a model system to investigate the biochemical signals that regulate these events. Multiple signaling proteins are phosphorylated in epithelial cells during hepatocyte growth factor–induced cell dispersal, including c-Cbl, a protooncogene docking protein with ubiquitin ligase activity. We have examined the role of c-Cbl and a transforming variant (70z-Cbl) in epithelial cell dispersal. We show that the expression of 70z-Cbl in Madin-Darby canine kidney epithelial cells resulted in the breakdown of cell–cell contacts and alterations in cell morphology characteristic of epithelial–mesenchymal transition. Structure–function studies revealed that the amino-terminal portion of c-Cbl, which corresponds to the Cbl phosphotyrosine-binding/Src homology domain 2 , is sufficient to promote the morphological changes in cell shape. Moreover, a point mutation at Gly-306 abrogates the ability of the Cbl Src homology domain 2 to induce these morphological changes. Our results identify a role for Cbl in the regulation of epithelial–mesenchymal transition, including loss of adherens junctions, cell spreading, and the initiation of cell dispersal.

scholarly journals The T Box Transcription Factor TBX2 Promotes Epithelial-Mesenchymal Transition and Invasion of Normal and Malignant Breast Epithelial Cells

PLoS ONE ◽  
2012 ◽  
Vol 7 (7) ◽  
pp. e41355 ◽  
Author(s):  
Bin Wang ◽  
Linsey E. Lindley ◽  
Virneliz Fernandez-Vega ◽  
Megan E. Rieger ◽  
Andrew H. Sims ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Epithelial Cells ◽  
Epithelial Mesenchymal Transition ◽  
Breast Epithelial Cells ◽  
Mesenchymal Transition ◽  
T Box ◽  
Malignant Breast ◽  
Breast Epithelial
Sign in / Sign up

Export Citation Format

Share Document