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 MiR-30b is involved in methylglyoxal-induced epithelial-mesenchymal transition of peritoneal mesothelial cells in rats

2014 ◽  
Vol 19 (2) ◽  
Author(s):  
Hong Liu ◽  
Ning Zhang ◽  
Da Tian
Keyword(s):  
Mirna Expression ◽  
Epithelial Mesenchymal Transition ◽  
Degradation Products ◽  
Mesothelial Cells ◽  
Control Group ◽  
Peritoneal Fibrosis ◽  
Expression Array ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells

AbstractEpithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (PMC) is a major contributor to the pathogenesis of peritoneal fibrosis. EMT is at least in part caused by repeated exposure to glucose degradation products (GDPs), such as methylglyoxal (MGO). MiRNA contributes greatly to the EMT of PMCs. In this study, we tried to profile whether differences exist between the peritoneal membrane (PM) miRNA expression seen in control rats and that seen in rats injected intraperitoneally with MGO. We assessed whether miR-30b has a possible role in MGO-induced EMT of PMCs in rats. Comparative miRNA expression array and real-time PCR analyses were conducted for the control group at the start of the experiment and for the MGO group after 1 and 2 weeks. During the second week, the MGO rats were treated with: a chemically modified antisense RNA oligonucleotide (ASO) complementary to the mature miR-30b (ASO group); an miR-30b mismatch control sequence (MIS group); or a citrate buffer (EMT group). Bioinformatic analyses indicated that the 3′ untranslated region (3′-UTR) of bone morphogenetic protein 7 (BMP7) mRNA did contain a putative binding site for miR-30b. We also tried to investigate whether miR-30b targeted BMP7 in vitro by transfection. Of the upregulated miRNAs, miR-30b expression demonstrated the greatest increase. The administration of miR-30b ASO for two weeks significantly reduced α-SMA excretion and upregulated E-cadherin and BMP-7 expression. Our in vitro study showed that miR-30b directly targeted and inhibited BMP7 by binding to its 3’-UTR. Our results revealed that miR-30b is involved in MGO-induced EMT of PMCs in rats.

scholarly journals miRNA589 Regulates Epithelial-Mesenchymal Transition in Human Peritoneal Mesothelial Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ke Zhang ◽  
Hao Zhang ◽  
Xun Zhou ◽  
Wen-bin Tang ◽  
Li Xiao ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Mesothelial Cell ◽  
Mesothelial Cells ◽  
Control Group ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells ◽  
Human Peritoneal Mesothelial Cells ◽  
E Cadherin

Background. microRNA (miRNA, miR) are thought to interact with multiple mRNAs which are involved in the EMT process. But the role of miRNAs in peritoneal fibrosis has remained unknown.Objective. To determine if miRNA589 regulates the EMT induced by TGFβ1 in human peritoneal mesothelial cell line (HMrSV5 cells).Methods. 1. Level of miR589 was detected in both human peritoneal mesothelial cells (HPMCs) isolated from continuous ambulatory peritoneal dialysis (CAPD) patients’ effluent and HMrSV5 cells treated with or without TGFβ1. 2. HMrSV5 cells were divided into three groups: control group, TGFβ1 group, and pre-miR-589+TGFβ1 group. The level of miRNA589 was determined by realtime PCR. The expressions of ZO-1, vimentin, and E-cadherin in HPMCs were detected, respectively.Results. Decreased level of miRNA589 was obtained in either HPMCs of long-term CAPD patients or HMrSV5 cells treated with TGFβ1. In vitro, TGFβ1 led to upregulation of vimentin and downregulation of ZO-1 as well as E-cadherin in HMrSV5 cells, which suggested EMT, was induced. The changes were accompanied with notably decreased level of miRNA589 in HMrSV5 cells treated with TGFβ1. Overexpression of miRNA589 by transfection with pre-miRNA589 partially reversed these EMT changes.Conclusion. miRNA589 mediates TGFβ1 induced EMT in human peritoneal mesothelial cells.

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.

scholarly journals Nintedanib inhibits the development and progression of peritoneal fibrosis

2020 ◽  
Author(s):  
Feng Liu ◽  
Chao Yu ◽  
Huan Qin ◽  
Shenglei Zhang ◽  
Lu Fang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Immunoblot Analysis ◽  
Nuclear Factor Κb ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells

Abstract Background Nintedanib, an FDA approved triple tyrosine kinase inhibitor, exhibits an antifibrotic effect in idiopathic pulmonary and renal fibrosis. Its effect on peritoneal fibrosis remains unexplored. Methods The present study investigated the effect of nintedanib on the development and progression of peritoneal fibrosis by administration fo nintedanib immediately after peritoneal injury or starting at day 21 of the injury in a in a mouse model of chlorhexidine gluconate-induced peritoneal fibrosis. Peritoneal fibrosis and associated mechanisms were examined by immunohistochemistry and immunoblot analysis. Results Administration of nintedanib immediately after peritoneal injury attenuated peritoneal fibrosis, whereas delayed administration of nintedanib not only halted the progression of peritoneal fibrosis, but also in part reversed the established fibrosis. Mechanistically studies showed that nintedanib inhibited injury-induced mesothelial-to-mesenchymal transition, expression of several cytokines/chemokines, vascularization and infiltration of macrophages to the injured peritoneum. Nintedanib also blocked phosphorylation of platelet derived growth factor receptor, fibroblast growth factor receptor, vascular endothelial growth factor receptor, and Src, downregulated expression of Snail and Twist, two transcription factors and inactivated several signaling pathways associated with peritoneal fibrosis, including Smad3, signal transducer and Activator of transcription 3, and nuclear factor-κB. Moreover, late treatment with nintedanib promoted expression of matrix metallopeptidase 2 and reduced expression of tissue inhibitor of metalloproteinases 2 in the injured peritoneum. Finally, nintedanib abrogated transforming growth factor β1–induced mesothelial-to-mesenchymal transition and phosphorylation of aforementioned signaling molecules in cultured human peritoneal mesothelial cells. Conclusions These results suggest that nintedanib may inhibit peritoneal fibrosis development and progression by blocking mesothelial-to-mesenchymal transition, inflammation, and angiogenesis, and partially reversed established peritoneal fibrosis through metalloproteinases-mediated extracellular matrix degradation. Therefore, nintedanib holds therapeutic potential for the prevention and treatment of peritoneal fibrosis.

scholarly journals HL156A, a novel AMP-activated protein kinase activator, is protective against peritoneal fibrosis in an in vivo and in vitro model of peritoneal fibrosis

2016 ◽  
Vol 310 (5) ◽  
pp. F342-F350 ◽  
Author(s):  
Kyung Don Ju ◽  
Hyo Jin Kim ◽  
Bodokhsuren Tsogbadrakh ◽  
Jinho Lee ◽  
Hyunjin Ryu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Protective Mechanism ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Amp Activated Protein Kinase

HL156A is a novel AMP-activated protein kinase (AMPK) activator. We aimed to investigate the protective mechanism of HL156A against peritoneal fibrosis (PF) in in vivo and in vitro models. The rat PF model was induced by daily intraperitoneally injection of chlorhexidine (CHX) solution containing 0.1% CHX gluconate and 15% ethanol for 4 wk. The rats in the treatment group were treated with HL156A (1 mg·kg−1·day−1). Control rats were injected with vehicle alone. In vitro, cultured rat peritoneal mesothelial cells (RPMCs) were treated with either high glucose (HG; 50 mM), normal glucose (NG; 5 mM), NG+HL156A, or HG+HL156A. HL156A in supplemented rats ameliorated peritoneal calcification, cocoon formation, bowel obstruction, and PF. Immunohistochemistry showed reduced fibronectin accumulation in the peritoneum of HL156A-treated rats compared with those injected with CHX alone. HL156A treatment of RPMCs inhibited HG-induced myofibroblast transdifferentiation and markers of epithelial-mesenchymal transition (EMT). Moreover, HL156A ameliorated HG-induced transforming growth factor-β1, Smad3, Snail, and fibronectin expression in the RPMCs via AMPK upregulation. These results suggest that HL156A exhibits a protective effect in PF progression. Further research is warranted to seek the therapeutic potential of HL156A as an antifibrotic agent in peritoneal dialysis patients.

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