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.

MiR-32-5p knockdown inhibits epithelial to mesenchymal transition and renal fibrosis by targeting SMAD7 in diabetic nephropathy

2020 ◽  
pp. 096032712095215
Author(s):  
H-J Wang ◽  
H Liu ◽  
Y-H Lin ◽  
S-J Zhang
Keyword(s):  
Diabetic Nephropathy ◽  
Renal Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Interstitial Fibrosis ◽  
Kidney Tissue ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Tubular Atrophy ◽  
Mesenchymal Transition ◽  
Gene Assay

Diabetic nephropathy (DN) is primary cause of end-stage renal disease. A previous study has shown that miR-32-5p (miR-32) is highly expressed in kidney tissue during chronic allograft dysfunction with interstitial fibrosis and tubular atrophy. However, the role of miR-32-5p (miR-32) in DN is still unclear. In this study, streptozotocin-induced DN rat models and high glucose (HG)-incubated human kidney proximal tubular epithelial (HK-2) cells were established to investigate the role and underlying mechanisms of miR-32 in DN. Results of real-time PCR revealed that miR-32 levels were greatly increased in DN rats and HG-incubated HK-2 cells. Downregulation of miR-32 effectively relieved HG-induced autophagy suppression, fibrosis, epithelial-mesenchymal transition (EMT) and inflammation in HK-2 cells. Besides, miR-32 overexpression significantly down-regulated the expression of mothers against decapentaplegic homolog 7 (SMAD7), whereas knockdown of miR-32 markedly up-regulated the level of SMAD7. Dual-luciferase reporter gene assay confirmed that SMAD7 was a target of miR-32. Reintroduction of SMAD7 expression rescued miR-32-induced HK-2 cells autophagy suppression, EMT and renal fibrosis. Our findings indicate that miR-32 may play roles in the progression of EMT and fibrosis in DN.

Oxidative stress as a common pathway to chronic tubulointerstitial injury in kidney allografts

2007 ◽  
Vol 293 (2) ◽  
pp. F445-F455 ◽  
Author(s):  
Arjang Djamali
Keyword(s):  
Oxidative Stress ◽  
Interstitial Fibrosis ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Common Mechanism ◽  
Placebo Control ◽  
Tubulointerstitial Injury ◽  
Tubular Atrophy ◽  
Mesenchymal Transition

A major challenge for kidney transplantation is to dissect out the identifiable causes of chronic allograft tubulointerstitial fibrosis and to develop cause-specific treatment strategies. There has been a recent interest in the role of oxidative stress (OS) as a mediator of injury in chronic allograft tubular atrophy (TA) and interstitial fibrosis (IF). A review of the literature and data from my laboratory studying chronic allograft TA/IF in rat, rhesus monkey, and human kidneys suggests that OS is increased in graft-infiltrating macrophages, activated myofibroblasts, interstitium, and areas of tubular injury. Chronic allograft OS may be induced by inflammation, abnormal tissue oxygenation, immunosuppressant drugs, and comorbid clinical conditions including diabetes, hypertension, proteinuria, anemia, and dyslipidemia. Moreover, OS-induced chronic TA/IF is associated with signaling pathways including inflammation, apoptosis, hypoxia, and epithelial-to-mesenchymal transition. Most of these injury pathways participate in a self-perpetuating cycle with OS. In conclusion, evidence suggests that OS is a common mechanism of injury in chronic allograft TA/IF. However, most available data demonstrate a correlation and no causal relationship. Furthermore, the extent to which TA/IF is dependent on OS is unknown. These questions may be answered by prospective randomized placebo-control trials examining the role of select antioxidants in the prevention of chronic allograft TA/IF.

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 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 Bortezomib limits renal allograft interstitial fibrosis by inhibiting NF-κB/TNF-α/Akt/mTOR/P70S6K/Smurf2 pathway via IκBα protein stabilization

2021 ◽  
Vol 135 (1) ◽  
pp. 53-69
Author(s):  
Chuanjian Suo ◽  
Zeping Gui ◽  
Zijie Wang ◽  
Jiajun Zhou ◽  
Ming Zheng ◽  
...  
Keyword(s):  
Renal Allograft ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Protein Stabilization ◽  
Mesenchymal Transition ◽  
P70s6 Kinase ◽  
Tnf Α

Abstract Chronic allograft dysfunction is a major cause of late graft failure after kidney transplantation. One of the histological changes is interstitial fibrosis, which is associated with epithelial–mesenchymal transition. Bortezomib has been reported to prevent the progression of fibrosis in organs. We used rat renal transplantation model and human kidney 2 cell line treated with tumor necrosis factor-α (TNF-α) to examine their response to bortezomib. To explore the mechanism behind it, we assessed the previously studied TNF-α/protein kinase B (Akt)/Smad ubiquitin regulatory factor 2 (Smurf2) signaling and performed RNA sequencing. Our results suggested that bortezomib could attenuate the TNF-α-induced epithelial–mesenchymal transition and renal allograft interstitial fibrosis in vitro and in vivo. In addition to blocking Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase/Smurf2 signaling, bortezomib’s effect on the epithelial–mesenchymal transition was associated with inhibition of nuclear factor kappa B (NF-κB) pathway by stabilizing inhibitor of NF-κB. The study highlighted the therapeutic potential of bortezomib on renal allograft interstitial fibrosis. Such an effect may result from inhibition of NF-κB/TNF-α/Akt/mTOR/p70S6 kinase/Smurf2 signaling via stabilizing protein of inhibitor of NF-κB.

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