scholarly journals PGC-1α Suppresses the Activation of TGF-β/Smad Signaling via Targeting TGFβRI Downregulation by let-7b/c Upregulation

2019 ◽  
Vol 20 (20) ◽  
pp. 5084 ◽  
Author(s):  
Hoon-In Choi ◽  
Jung Sun Park ◽  
Dong-Hyun Kim ◽  
Chang Seong Kim ◽  
Eun Hui Bae ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Peroxisome Proliferator ◽  
Major Pathway ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Smad Signaling Pathway ◽  
Signaling Activation

TGF-β/Smad signaling is a major pathway in progressive fibrotic processes, and further studies on the molecular mechanisms of TGF-β/Smad signaling are still needed for their therapeutic targeting. Recently, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) was shown to improve renal fibrosis, making it an attractive target for chronic kidney diseases (CKDs). Here, we show the mechanism by which PGC-1α regulates the TGF-β/Smad signaling pathway using HK-2 cell lines stably overexpressing empty vector (mock cells) or human PGC1α (PGC1α cells). Stable PGC-1α overexpression negatively regulated the expression of TGF-β-induced epithelial-mesenchymal transition (EMT) markers (fibronectin, E-cadherin, vimentin, and α-SMA) and EMT-related transcription factors (Snail and Slug) compared to mock cells, inhibiting fibrotic progression. Interestingly, among molecules upstream of Smad2/3 activation, the gene expression of only TGFβRI, but not TGFβRII, was downregulated in PGC-1α cells. In addition, the downregulation of TGFβRI by PGC-1α was associated with the upregulation of let-7b/c, miRNA for which the 3′ untranslated region (UTR) of TGFβRI contains a binding site. In conclusion, PGC-1α suppresses TGF-β/Smad signaling activation via targeting TGFβRI downregulation by let-7b/c upregulation.

scholarly journals Fenofibrate Improved Interstitial Fibrosis of Renal Allograft through Inhibited Epithelial-Mesenchymal Transition Induced by Oxidative Stress

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Yishu Wang ◽  
Lei Pang ◽  
Yanghe Zhang ◽  
Jiahui Lin ◽  
Honglan Zhou
Keyword(s):  
Oxidative Stress ◽  
Rat Model ◽  
Renal Allograft ◽  
Epithelial Mesenchymal Transition ◽  
Interstitial Fibrosis ◽  
Peroxisome Proliferator ◽  
Tubular Atrophy ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mesenchymal Transition ◽  
Stage Renal Disease

The best treatment for end-stage renal disease is renal transplantation. However, it is often difficult to maintain a renal allograft healthy for a long time following transplantation. Interstitial fibrosis and tubular atrophy (IF/TA) are significant histopathologic characteristics of a compromised renal allograft. There is no effective therapy to improve renal allograft function once IF/TA sets in. Although there are many underlying factors that can induce IF/TA, the pathogenesis of IF/TA has not been fully elucidated. It has been found that epithelial-mesenchymal transition (EMT) significantly contributes to the development of IF/TA. Oxidative stress is one of the main causes that induce EMT in renal allografts. In this study, we have used H2O2 to induce oxidative stress in renal tubular epithelial cells (NRK-52e) of rats. We also pretreated NRK-52e cells with an antioxidant (N-acetyl L-cysteine (NAC)) 1 h prior to the treatment with H2O2. Furthermore, we used fenofibrate (a peroxisome proliferator-activated receptor α agonist) to treat NRK-52e cells and a renal transplant rat model. Our results reveal that oxidative stress induces EMT in NRK-52e cells, and pretreatment with NAC can suppress EMT in these cells. Moreover, fenofibrate suppresses fibrosis by ameliorating oxidative stress-induced EMT in a rat model. Thus, fenofibrate may effectively prevent the development of fibrosis in renal allograft and improve the outcome.

scholarly journals Curcumin Suppresses Intestinal Fibrosis by Inhibition of PPARγ-Mediated Epithelial-Mesenchymal Transition

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Su Xu ◽  
Bin Jiang ◽  
Hui Wang ◽  
Cunsi Shen ◽  
Hao Chen ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Peroxisome Proliferator ◽  
Colon Tissue ◽  
Peroxisome Proliferator Activated Receptor ◽  
Smad Pathway ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis ◽  
E Cadherin

Intestinal fibrotic stricture is a major complication of Crohn’s disease (CD) and epithelial-to-mesenchymal transition (EMT) is considered as an important contributor to the formation of intestinal fibrosis by increasing extracellular matrix (ECM) proteins. Curcumin, a compound derived from rhizomes ofCurcuma, has been demonstrated with a potent antifibrotic effect. However, its effect on intestinal fibrosis and the potential mechanism is not completely understood. Here we found that curcumin pretreatment significantly represses TGF-β1-induced Smad pathway and decreases its downstreamα-smooth muscle actin (α-SMA) gene expression in intestinal epithelial cells (IEC-6); in contrast, curcumin increases expression of E-cadherin and peroxisome proliferator-activated receptorγ(PPARγ) in IEC-6. Moreover, curcumin promotes nuclear translocation of PPARγand the inhibitory effect of curcumin on EMT could be reversed by PPARγantagonist GW9662. Consistently, in the rat model of intestinal fibrosis induced by 2,4,5-trinitrobenzene sulphonic acid (TNBS), oral curcumin attenuates intestinal fibrosis by increasing the expression of PPARγand E-cadherin and decreasing the expression ofα-SMA, FN, and CTGF in colon tissue. Collectively, these results indicated that curcumin is able to prevent EMT progress in intestinal fibrosis by PPARγ-mediated repression of TGF-β1/Smad pathway.

scholarly journals Tangzhiqing Granules Alleviate Podocyte Epithelial-Mesenchymal Transition in Kidney of Diabetic Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Haiyan Xu ◽  
Xu Wang ◽  
Mingming Liu ◽  
Xueyuan He
Keyword(s):  
Molecular Markers ◽  
Treatment Group ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Diabetic Rats ◽  
High Dose ◽  
Mesenchymal Transition ◽  
Dose Treatment ◽  
Smad Signaling ◽  
Smad Signaling Pathway

This study discussed the effect of Tangzhiqing granules on podocyte epithelial-mesenchymal transition in kidney of diabetic rats. The diabetic rats were divided randomly into five groups: DM group treated with vehicle, Tangzhiqing granules low-dose treatment group, Tangzhiqing granules middle-dose treatment group, and Tangzhiqing granules high-dose treatment group. Eight Wistar rats used as control group were given saline solution. The intervention was all intragastric administration for 8 weeks. At the end of the 8 weeks, biochemical parameters and kidney weight/body weight ratio were measured. The kidney tissues were observed under light microscope and transmission electron microscopy. To search for the underlying mechanism, we examined the epithelial-to-mesenchymal transition (EMT) related molecular markers and TGF-β/smad signaling pathway key proteins expression. The results showed that Tangzhiqing granules relieved the structural damage and functional changes of diabetic kidneys. Kidney podocyte EMT related molecular markers nephrin and CD2AP expression were increased, when desmin and α-SMA levels were decreased by Tangzhiqing granules in diabetic rats. Further TGF-β/smad signaling pathway key proteins TGF-β1 and p-smad2/3 levels were decreased in diabetic rats after treatment with Tangzhiqing granules. These findings suggest that Tangzhiqing granules may protect the podocytes of diabetic nephropathy rats via alleviating podocyte EMT and likely activating TGFβ/smad signaling pathway.

scholarly journals DcR3 induces epithelial-mesenchymal transition through activation of the TGF-β3/SMAD signaling pathway in CRC

Oncotarget ◽  
2016 ◽  
Vol 7 (47) ◽  
pp. 77306-77318 ◽  
Author(s):  
Yan-Ping Liu ◽  
Hui-Fang Zhu ◽  
Ding-li Liu ◽  
Zhi-Yan Hu ◽  
Sheng-Nan Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Smad Signaling Pathway
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