scholarly journals Nitro-oleic acid inhibits the high glucose-induced epithelial-mesenchymal transition in peritoneal mesothelial cells and attenuates peritoneal fibrosis

2020 ◽  
Vol 318 (2) ◽  
pp. F457-F467
Author(s):  
Wenyan Su ◽  
Haiping Wang ◽  
ZiYan Feng ◽  
Jing Sun
Keyword(s):  
Peritoneal Dialysis ◽  
Oleic Acid ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Muscle Actin ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells

As an electrophilic nitroalkene fatty acid, nitro-oleic acid (OA-NO2) exerts multiple biological effects that contribute to anti-inflammation, anti-oxidative stress, and antiapoptosis. However, little is known about the role of OA-NO2 in peritoneal fibrosis. Thus, in the present study, we examined the effects of OA-NO2 on the high glucose (HG)-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMCs) and evaluated the morphological and immunohistochemical changes in a rat model of peritoneal dialysis-related peritoneal fibrosis. In in vitro experiments, we found that HG reduced the expression level of E-cadherin and increased Snail, N-cadherin, and α-smooth muscle actin expression levels in HPMCs. The above-mentioned changes were attenuated by pretreatment with OA-NO2. Additionally, OA-NO2 also inhibited HG-induced activation of the transforming growth factor-β1/Smad signaling pathway and NF-κB signaling pathway. Meanwhile, OA-NO2 inhibited HG-induced phosphorylation of Erk and JNK. The results from the in vivo experiments showed that OA-NO2 notably relieved peritoneal fibrosis by decreasing the thickness of the peritoneum; it also inhibited expression of transforming growth factor-β1, α-smooth muscle actin, N-cadherin, and vimentin and enhanced expression of E-cadherin in the peritoneum. Collectively, these results suggest that OA-NO2 inhibits the HG-induced epithelial-mesenchymal transition in HPMCs and attenuates peritoneal dialysis-related peritoneal fibrosis.

Transforming Growth Factor β1 Induces Epithelial–mesenchymal Transition by Activating the Jnk–SMAD3 Pathway in Rat Peritoneal Mesothelial Cells

2008 ◽  
Vol 28 (3_suppl) ◽  
pp. 88-95 ◽  
Author(s):  
Qinghua Liu ◽  
Haiping Mao ◽  
Jing Nie ◽  
Wei Chen ◽  
Qiongqiong Yang ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β1 ◽  
Collagen I ◽  
Peritoneal Fibrosis ◽  
Jnk Signaling ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Smad Proteins ◽  
E Cadherin

⋄ Background Peritoneal fibrosis is a serious complication in long-term peritoneal dialysis (PD) patients. Epithelial-mesenchymal transition (EMT) plays an important role in peritoneal fibrosis, and TGFβ1 is the crucial inducer of EMT. Phosphorylation of Smad proteins is required for TGFβ1-induced EMT. It was reported that C-Jun N-terminal kinase (JNK) was involved in the TGFβ1/Smad signaling pathway and might regulate the activation of Smad proteins. However, whether JNK is activated by TGFβ1 in rat peritoneal mesothelial cells (RPMCs) and the role taken by JNK signaling in EMT induced by TGFβ1 remains undetermined. In the present study, we investigated the role of JNK-Smad pathway in EMT induced by TGFβ1 in RPMCs. ⋄ Methods We harvested RPMCs from the peritoneum of male Sprague-Dawley rats and then cultured the cells in Dulbecco modified Eagle medium / F12 medium with 15% (volume:volume) fetal bovine serum. The cells were pretreated with SP600125, a specific inhibitor of JNK, for 4 hours before incubation with TGFβ1. The protein expression levels of phosphorylated JNK, Smad2, and Smad3 were detected by Western blotting. The messenger RNA levels and protein expression of α-smooth muscle actin (α-SMA), E-cadherin, and collagen I were determined with reverse transcriptase polymerase chain reaction and Western blotting respectively. ⋄ Results Expression of α-SMA and collagen I were significantly increased and expression of E-cadherin decreased with TGFβ1 in RPMCs. Transforming growth factor β1 can stimulate phosphorylated JNK expression from 5 minutes, with the peak at 10 minutes, and phosphorylated Smad2 and Smad3 expression from 10 minutes, with the peak at 30 minutes. The addition of SP600125, which blocked activation of JNK, effectively inhibited TGFβ1-induced phosphorylation of Smad3, but not Smad2. Also, our results showed that SP600125 effectively suppressed TGFβ1-induced high expression of α-SMA and collagen I, and prevented TGFβ1-induced downregulation of E-cadherin expression in RPMCs. ⋄ Conclusions This study demonstrated that JNK signaling may play an important role in EMT induced by TGFβ1 in RPMCs through activation of Smad3, suggesting that JNK inhibitor may prove to be a novel therapeutic agent for peritoneal fibrosis.

Central role for Rho in TGF-β1-induced α-smooth muscle actin expression during epithelial-mesenchymal transition

2003 ◽  
Vol 284 (5) ◽  
pp. F911-F924 ◽  
Author(s):  
András Masszi ◽  
Caterina Di Ciano ◽  
Gábor Sirokmány ◽  
William T. Arthur ◽  
Ori D. Rotstein ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Stress Fiber ◽  
Small Gtpase ◽  
Cell Contact ◽  
Muscle Actin ◽  
Mesenchymal Transition ◽  
Fiber Assembly

New research suggests that, during tubulointerstitial fibrosis, α-smooth muscle actin (SMA)-expressing mesenchymal cells might derive from the tubular epithelium via epithelial-mesenchymal transition (EMT). Although transforming growth factor-β1(TGF-β1) plays a key role in EMT, the underlying cellular mechanisms are not well understood. Here we characterized TGF-β1-induced EMT in LLC-PK1 cells and examined the role of the small GTPase Rho and its effector, Rho kinase, (ROK) in the ensuing cytoskeletal remodeling and SMA expression. TGF-β1 treatment caused delocalization and downregulation of cell contact proteins (ZO-1, E-cadherin, β-catenin), cytoskeleton reorganization (stress fiber assembly, myosin light chain phosphorylation), and robust SMA synthesis. TGF-β1induced a biphasic Rho activation. Stress fiber assembly was prevented by the Rho-inhibiting C3 transferase and by dominant negative (DN) ROK. The SMA promoter was activated strongly by constitutively active Rho but not ROK. Accordingly, TGF-β1-induced SMA promoter activation was potently abrogated by two Rho-inhibiting constructs, C3 transferase and p190RhoGAP, but not by DN-ROK. Truncation analysis showed that the first CC(A/T)richGG (CArG B) serum response factor-binding cis element is essential for the Rho responsiveness of the SMA promoter. Thus Rho plays a dual role in TGF-β1-induced EMT of renal epithelial cells. It is indispensable both for cytoskeleton remodeling and for the activation of the SMA promoter. The cytoskeletal effects are mediated via the Rho/ROK pathway, whereas the transcriptional effects are partially ROK independent.

scholarly journals Inhibition of TGF-β2-induced migration and epithelial-mesenchymal transition in ARPE-19 by sulforaphane

2021 ◽  
Vol 14 (7) ◽  
pp. 973-980
Author(s):  
Yan-Bing Huang ◽  
◽  
Hui Zheng ◽  
Xiu-Xia Yang ◽  
Cheng-Cheng Yang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Fiber Formation ◽  
Stress Fibers ◽  
Actin Stress Fiber ◽  
Muscle Actin ◽  
Mesenchymal Transition ◽  
Actin Stress Fibers

AIM: To investigate the effects of sulforaphane (SFN) on transforming growth factor (TGF)-β2 stimulated migration and epithelial-mesenchymal transition (EMT) in ARPE-19 cells. METHODS: ARPE-19 cells were cultured in the presence or absence of SFN or TGF-β2. SFN toxicity was assessed by performing a lactate dehydrogenase assay (LDH) and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assays, and cell migration was evaluated by Transwell migration assay. Actin stress fiber formation in ARPE-19 cells was determined using immunofluorescence analysis. Immunoblotting analysis was used to determine fibronectin and α-smooth muscle actin expressions along with the degree of Smad and Akt phosphorylation. RESULTS: SFN inhibited ARPE-19 migration. Additionally, SFN attenuated TGF-β2-induced appearance of actin stress fibers as well as fibronectin and α-smooth muscle actin expressions in these cells. SFN also hindered the TGF-β2-stimulated phosphorylation of Smad2, Smad3, and Akt. SFN showed no cytotoxicity towards ARPE-19 cells. CONCLUSION: SFN inhibits TGF-β2-stimulated migration and EMT in ARPE-19 cells, probably by preventing the establishment of actin stress fibers and Akt and Smad2/3 signaling.

scholarly journals Dynamic actin remodeling during epithelial–mesenchymal transition depends on increased moesin expression

2011 ◽  
Vol 22 (24) ◽  
pp. 4750-4764 ◽  
Author(s):  
Jennifer Haynes ◽  
Jyoti Srivastava ◽  
Nikki Madson ◽  
Torsten Wittmann ◽  
Diane L. Barber
Keyword(s):  
Epithelial Cells ◽  
Actin Filament ◽  
Actin Filaments ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Mammary Epithelial Cells ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Mammary Epithelial ◽  
Mesenchymal Transition

Remodeling of actin filaments is necessary for epithelial–mesenchymal transition (EMT); however, understanding of how this is regulated in real time is limited. We used an actin filament reporter and high-resolution live-cell imaging to analyze the regulated dynamics of actin filaments during transforming growth factor-β–induced EMT of mammary epithelial cells. Progressive changes in cell morphology were accompanied by reorganization of actin filaments from thin cortical bundles in epithelial cells to thick, parallel, contractile bundles that disassembled more slowly but remained dynamic in transdifferentiated cells. We show that efficient actin filament remodeling during EMT depends on increased expression of the ezrin/radixin/moesin (ERM) protein moesin. Cells suppressed for moesin expression by short hairpin RNA had fewer, thinner, and less stable actin bundles, incomplete morphological transition, and decreased invasive capacity. These cells also had less α-smooth muscle actin and phosphorylated myosin light chain in cortical patches, decreased abundance of the adhesion receptor CD44 at membrane protrusions, and attenuated autophosphorylation of focal adhesion kinase. Our findings suggest that increased moesin expression promotes EMT by regulating adhesion and contractile elements for changes in actin filament organization. We propose that the transciptional program driving EMT controls progressive remodeling of actin filament architectures.

scholarly journals MiR-200a negatively regulates TGF-β1-induced epithelial-mesenchymal transition of peritoneal mesothelial cells by targeting ZEB1/2 expression

2018 ◽  
Vol 314 (6) ◽  
pp. F1087-F1095 ◽  
Author(s):  
Runsheng Guo ◽  
Guojun Hao ◽  
Yi Bao ◽  
Jun Xiao ◽  
Xiaojiang Zhan ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
De Novo ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Mesothelial Cells ◽  
Peritoneal Fibrosis ◽  
Close Link ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Collagen Expression

Although epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells was recognized as the key process of peritoneal fibrosis, which is a major cause of peritoneal failure related to peritoneal dialysis (PD), mechanisms underlying these processes remain largely unknown. In this study, we found that miR-200a was significantly downregulated in peritoneal tissues with fibrosis in a rat model of PD. In vitro, transforming growth factor (TGF)-β1-induced EMT, identified by de novo expression of α-smooth muscle actin and a loss of E-cadherin in human peritoneal mesothelial cells (HPMCs), was associated with downregulation of miR-200a but upregulation of zinc finger E-box-binding homeobox 1/2 (ZEB1/2), suggesting a close link between miR-200a and ZEB1/2 in TGF-β1-induced EMT. It was further demonstrated that miR-200a was able to bind to the 3′UTR of ZEB1/2, and overexpression of miR-200a blocked TGF-β1-induced upregulation of ZEB1/2 and, therefore, inhibited EMT and collagen expression. In contrast, overexpression ZEB1/2 blocked miR-200a inhibition of EMT and collagen expression in HMPCs. In conclusion, miR-200a could negatively regulate TGF-β1-induced EMT by targeting ZEB1/2 in peritoneal mesothelial cells. Blockade of EMT in HPMCS indicates the therapeutic potential of miR-200a as a treatment for peritoneal fibrosis associated with PD.

scholarly journals The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 476 ◽  
Author(s):  
Chia-Jung Li ◽  
Pei-Yi Chu ◽  
Giou-Teng Yiang ◽  
Meng-Yu Wu
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Inhibition Of Proliferation ◽  
Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

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