Epithelial-to-mesenchymal transition of peritoneal mesothelial cells is regulated by an ERK/NF-κB/Snail1 pathway

Abstract

SUMMARYEpithelial-to-mesenchymal transition (EMT) occurs in fibrotic diseases affecting the kidney, liver and lung, and in the peritoneum of patients undergoing peritoneal dialysis. EMT in the peritoneum is linked to peritoneal membrane dysfunction, and its establishment limits the effectiveness of peritoneal dialysis. The molecular regulation of EMT in the peritoneum is thus of interest from basic and clinical perspectives. Treatment of primary human mesothelial cells (MCs) with effluent from patients undergoing peritoneal dialysis induced a genuine EMT, characterized by downregulated E-cadherin and cytokeratin expression, cell scattering, and spindle-like morphology. This EMT was replicated by co-stimulation with transforming growth factor (TGF)-β1 and interleukin (IL)-1β. Retroviral overexpression of a mutant inhibitor of kappaB (IκB) demonstrated that NF-κB activation is required for E-cadherin and cytokeratin downregulation during EMT. Pre-treatment with the MAP kinase kinase (MEK)-1/2 inhibitor U0126 showed that cytokinetriggered NF-κB nuclear translocation and transcriptional activity are mediated by activation of extracellular regulated kinase (ERK). Cytokine-mediated induction of mRNA expression of the transcription factor Snail1, a repressor of E-cadherin expression and a potent inducer of EMT, was prevented by blockade of ERK or NF-κB. Finally, blockade of ERK/NF-κB signaling in ex vivo MCs that were cultured from peritoneal dialysis effluents reverted cells to an epithelioid morphology, upregulated E-cadherin and cytokeratin expression, and downregulated Snail1 expression. Modulation of the ERK/NF-κB/Snail1 pathway may provide a means of counteracting the progressive structural and functional deterioration of the peritoneal membrane during peritoneal dialysis.

PPAR-γ agonist rosiglitazone protects peritoneal membrane from dialysis fluid-induced damage

“…In our previous studies, in an attempt to mimic the complex mixture of pro-inflammatory and pro-fibrotic stimuli induced during PD, we used a combination of TGF-b1 and IL-1b to induce MMT in vitro. 10,14,15,44 We demonstrated that the treatment of mesothelial cells with TGF-b1 is sufficient to induce their mesenchymal conversion, and that the combination of TGFb1 and IL-1b has additive effect on the MMT process. 10,44 In this study, we demonstrate that RSG does not block the MMT induced by TGF-b1 alone, thus it is not expected that Figure 6 Effect of RSG treatment on submesothelial recruitment of CD45 þ cells.…”

“…10,14,15,44 We demonstrated that the treatment of mesothelial cells with TGF-b1 is sufficient to induce their mesenchymal conversion, and that the combination of TGFb1 and IL-1b has additive effect on the MMT process. 10,44 In this study, we demonstrate that RSG does not block the MMT induced by TGF-b1 alone, thus it is not expected that Figure 6 Effect of RSG treatment on submesothelial recruitment of CD45 þ cells. Mice received a daily instillation of standard PD fluid for 3 weeks with or without the oral adminstraton of RSG (PDF, n ¼ 12 and PDF þ RSG n ¼ 11).…”

Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial–mesenchymal transition in liver injury

“…MCs have a phenotype intermediate between epithelial and mesenchymal cells, expressing markers indicative of both cell types. Recent studies in patients with peritoneal fibrosis following peritoneal dialysis for treatment of kidney failure suggest that peritoneal MCs undergo epithelial mesenchymal transition (EMT) and give rise to myofibroblasts (3). EMT is a process by which epithelial cells lose their polarity and gain migratory capacity in embryogenesis, tissue repair, organ fibrosis, and tumor invasion and metastasis (4).…”

“…EMT is a process by which epithelial cells lose their polarity and gain migratory capacity in embryogenesis, tissue repair, organ fibrosis, and tumor invasion and metastasis (4). TGF-β signaling, implicated in EMT, suppresses expression of E-cadherin (CDH1), Zo1 (TJP1), and cytokeratin (KRT) while inducing vimentin (VIM) and α-smooth muscle actin (ACTA2) in peritoneal MCs (3,5).…”

Ras Promotes Transforming Growth Factor-β (TGF-β)-induced Epithelial-Mesenchymal Transition via a Leukotriene B4 Receptor-2-linked Cascade in Mammary Epithelial Cells

“…snail and ZEB1/2). For example, it was reported that the activation of Snail transcription requires NF-B; the Snail promoter has functional NF-B sites (38), and the inhibition of NF-B significantly reduced Snail transcription (39,40). In addition, Chua et al (41) reported that NF-B suppresses the expression of E-cadherin and induces the expression of the mesenchymespecific gene vimentin in MCF-10A cells through ZEB1/2.…”