MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway

2018 ◽  
Vol 132 (21) ◽  
pp. 2339-2355 ◽  
Author(s):  
Zhenzhen Li ◽  
Xianghua Liu ◽  
Fengyan Tian ◽  
Ji Li ◽  
Qingwei Wang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Mitogen Activated Protein Kinase ◽  
Jnk Signaling ◽  
Mesenchymal Transition ◽  
Amino Terminal ◽  
Ureter Obstruction ◽  
Tgf Β1

Epithelial-to-mesenchymal transition (EMT) is a phenotypic conversion that plays a crucial role in renal fibrosis leading to chronic renal failure. Mitogen-activated protein kinase phosphatase 2 (MKP2) is a member of the dual-specificity MKPs that regulate the MAP kinase pathway involved in transforming growth factor-β1 (TGF-β1)-induced EMT. However, the function of MKP2 in the regulation of EMT and the underlying mechanisms are still largely unknown. In the present study, we detected the expression of MKP2 in an animal model of renal fibrosis and evaluated the potential role of MKP2 in tubular EMT induced by TGF-β1. We found that the expression of MKP2 was up-regulated in the tubular epithelial of unilateral ureter obstruction rats. Meanwhile, we also demonstrated that TGF-β1 up-regulated MKP2 expression in NRK-52E cells during their EMT phenotype acquisition. Importantly, overexpression of MKP2 inhibited c-Jun amino terminal kinase (JNK) signaling and partially reversed EMT induced by TGF-β1. Moreover, reducing MKP2 expression enhanced JNK phosphorylation, promoted the E-cadherin suppression and induced α-SMA expression and fibronectin secretion in response to TGF-β1, which could be rescued by a JNK inhibitor. These results provide the first evidence that MKP2 is a negative feedback molecule induced by TGF-β1, and MKP2 overexpression inhibits TGF-β1-induced EMT through the JNK signaling pathway. MKP2 could be a promising target to be used in gene therapy for renal fibrosis.

MKP2 suppresses TGF-β1-induced epithelial-to-mesenchymal transition through JNK inhibition

2019 ◽  
Vol 133 (3) ◽  
pp. 545-550 ◽  
Author(s):  
Ivonne Loeffler
Keyword(s):  
Protein Kinase ◽  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Renal Diseases ◽  
Line System ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein ◽  
Tgf Β1

Abstract Interstitial fibrosis is a typical feature of end-stage renal diseases, regardless of the initial cause of kidney injury. Epithelial-to-mesenchymal transition (EMT) is a mechanism that is thought to play a role in generating the interstitial matrix-producing myofibroblasts and is prominently induced by the transforming growth factor-β 1 (TGF-β1). TGF-β1 signals through a variety of Smad and non-Smad signaling pathways, including the mitogen-activated protein kinase (MAPK) pathways. In a study published in a recent issue of Clinical Science (Clin. Sci. (2018) 132(21),2339–2355), Li et al. investigated the potential role of the Mitogen-activated protein kinase phosphatase 2 (MKP2), also known as Dusp4, in the control of EMT and renal fibrosis. Based on results obtained with an animal model of kidney fibrosis and a proximal tubular epithelial cell line system, the authors put forward a role for MKP2 as a negative feedback regulator of TGF-β1-induced EMT and fibrosis in the kidney. Intriguingly, MKP2 is found to down-regulate activity of c-Jun, but not that of other MAPKs, extracellular signal-regulated kinases or p38, implying a role for c-Jun N-terminal kinase-dependent signaling in renal fibrosis. In this commentary, I discuss the findings of Li and co-workers in the context of the recent literature placing a focus on potential clinical/therapeutic implications.

scholarly journals Targeted DNA oxidation by LSD1–SMAD2/3 primes TGF-β1/ EMT genes for activation or repression

2020 ◽  
Vol 48 (16) ◽  
pp. 8943-8958 ◽  
Author(s):  
Antonio Pezone ◽  
Maria Letizia Taddei ◽  
Alfonso Tramontano ◽  
Jacopo Dolcini ◽  
Francesca Ludovica Boffo ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Dna Oxidation ◽  
Mesenchymal Transition ◽  
Kinase C ◽  
Histone Lysine ◽  
Lysine Specific Demethylase ◽  
Tgf Β1

Abstract The epithelial-to-mesenchymal transition (EMT) is a complex transcriptional program induced by transforming growth factor β1 (TGF-β1). Histone lysine-specific demethylase 1 (LSD1) has been recognized as a key mediator of EMT in cancer cells, but the precise mechanism that underlies the activation and repression of EMT genes still remains elusive. Here, we characterized the early events induced by TGF-β1 during EMT initiation and establishment. TGF-β1 triggered, 30–90 min post-treatment, a nuclear oxidative wave throughout the genome, documented by confocal microscopy and mass spectrometry, mediated by LSD1. LSD1 was recruited with phosphorylated SMAD2/3 to the promoters of prototypic genes activated and repressed by TGF-β1. After 90 min, phospho-SMAD2/3 downregulation reduced the complex and LSD1 was then recruited with the newly synthesized SNAI1 and repressors, NCoR1 and HDAC3, to the promoters of TGF-β1-repressed genes such as the Wnt soluble inhibitor factor 1 gene (WIF1), a change that induced a late oxidative burst. However, TGF-β1 early (90 min) repression of transcription also required synchronous signaling by reactive oxygen species and the stress-activated kinase c-Jun N-terminal kinase. These data elucidate the early events elicited by TGF-β1 and the priming role of DNA oxidation that marks TGF-β1-induced and -repressed genes involved in the EMT.

scholarly journals Melatonin Inhibits Transforming Growth Factor-β1-Induced Epithelial–Mesenchymal Transition in AML12 Hepatocytes

Biology ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 84 ◽  
Author(s):  
Kim ◽  
Park ◽  
Kim ◽  
Leem ◽  
Park
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Protective Action ◽  
Transforming Growth Factor Β1 ◽  
Membrane Receptors ◽  
Mitogen Activated Protein Kinase ◽  
Independent Manner ◽  
Mesenchymal Transition ◽  
Tgf Β1

Recent studies showed that melatonin, a well-known pineal hormone that modulates the circadian rhythm, exerts beneficial effects against liver fibrosis. However, mechanisms for its protective action against the fibrotic processes remain incompletely understood. Here, we aimed to explore the effects of the hormone on transforming growth factor-β1 (TGF-β1)-stimulated epithelial–mesenchymal transition (EMT) in AML12 hepatocytes. Pretreatment with melatonin dose-dependently reversed downregulation of an epithelial marker and upregulation of mesenchymal markers after TGF-β1 stimulation. Additionally, melatonin dose-dependently suppressed an increased phosphorylation of Smad2/3 after TGF-β1 treatment. Besides the canonical Smad signaling pathway, an increase in phosphorylation of extracellular signal-regulated kinase 1/2 and p38 was also dose-dependently attenuated by melatonin. The suppressive effect of the hormone on EMT stimulated by TGF-β1 was not affected by luzindole, an antagonist of melatonin membrane receptors, suggesting that its membrane receptors are not required for the inhibitory action of melatonin. Moreover, melatonin suppressed elevation of intracellular reactive oxygen species (ROS) levels in TGF-β1-treated cells. Finally, TGF-β1-stimulated EMT was also inhibited by the antioxidant N-acetylcysteine. Collectively, these results suggest that melatonin prevents TGF-β1-stimulated EMT through suppression of Smad and mitogen-activated protein kinase signaling cascades by deactivating ROS-dependent mechanisms in a membrane receptor-independent manner.

Epigenetic regulation of TGF-β1 signalling in dilative aortopathy of the thoracic ascending aorta

2016 ◽  
Vol 130 (16) ◽  
pp. 1389-1405 ◽  
Author(s):  
Amalia Forte ◽  
Umberto Galderisi ◽  
Marilena Cipollaro ◽  
Marisa De Feo ◽  
Alessandro Della Corte
Keyword(s):  
Gene Expression ◽  
Epigenetic Regulation ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Transforming Growth Factor Β1 ◽  
Ascending Aorta ◽  
Mesenchymal Transition ◽  
Aorta Dilatation ◽  
Tgf Β1

The term ‘epigenetics’ refers to heritable, reversible DNA or histone modifications that affect gene expression without modifying the DNA sequence. Epigenetic modulation of gene expression also includes the RNA interference mechanism. Epigenetic regulation of gene expression is fundamental during development and throughout life, also playing a central role in disease progression. The transforming growth factor β1 (TGF-β1) and its downstream effectors are key players in tissue repair and fibrosis, extracellular matrix remodelling, inflammation, cell proliferation and migration. TGF-β1 can also induce cell switch in epithelial-to-mesenchymal transition, leading to myofibroblast transdifferentiation. Cellular pathways triggered by TGF-β1 in thoracic ascending aorta dilatation have relevant roles to play in remodelling of the vascular wall by virtue of their association with monogenic syndromes that implicate an aortic aneurysm, including Loeys–Dietz and Marfan's syndromes. Several studies and reviews have focused on the progression of aneurysms in the abdominal aorta, but research efforts are now increasingly being focused on pathogenic mechanisms of thoracic ascending aorta dilatation. The present review summarizes the most recent findings concerning the epigenetic regulation of effectors of TGF-β1 pathways, triggered by sporadic dilative aortopathy of the thoracic ascending aorta in the presence of a tricuspid or bicuspid aortic valve, a congenital malformation occurring in 0.5–2% of the general population. A more in-depth comprehension of the epigenetic alterations associated with TGF-β1 canonical and non-canonical pathways in dilatation of the ascending aorta could be helpful to clarify its pathogenesis, identify early potential biomarkers of disease, and, possibly, develop preventive and therapeutic strategies.

scholarly journals Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-β1

2017 ◽  
Vol 313 (4) ◽  
pp. F961-F972 ◽  
Author(s):  
Junpeng Wang ◽  
Yang Chen ◽  
Di Gu ◽  
Guihao Zhang ◽  
Jiawei Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Bladder Wall ◽  
Transforming Growth Factor Β1 ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Tgf Β1

Bladder wall fibrosis is a major complication of ketamine-induced cystitis (KC), but the underlying pathogenesis is poorly understood. The aim of the present study was to elucidate the mechanism of ketamine-induced fibrosis in association with epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor-β1 (TGF-β1). Sprague-Dawley rats were randomly distributed into four groups, which received saline, ketamine, ketamine combined with a TGF-β receptor inhibitor (SB-505124) for 16 wk, or 12 wk of ketamine and 4 wk of abstinence. In addition, the profibrotic effect of ketamine was confirmed in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. The ketamine-treated rats displayed voiding dysfunction and decreased bladder compliance. Bladder fibrosis was accompanied by the appearance of a certain number of cells expressing both epithelial and mesenchymal markers, indicating that epithelial cells might undergo EMT upon ketamine administration. Meanwhile, the expression level of TGF-β1 was significantly upregulated in the urothelium of bladders in ketamine-treated rats. Treatment of SV-HUC-1 cells with ketamine increased the expression of TGF-β1 and EMT-inducing transcription factors, resulting in the downregulation of E-cadherin and upregulation of fibronectin and α-smooth muscle actin. Administration of SB-505124 inhibited EMT and fibrosis both in vitro and vivo. In addition, withdrawal from ketamine did not lead to recovery of bladder urinary function or decreased fibrosis. Taken together, our study shows for the first time that EMT might contribute to bladder fibrosis in KC. TGF-β1 may have an important role in bladder fibrogenesis via an EMT mechanism.

scholarly journals Metformin Improves Epithelial-to-Mesenchymal Transition Induced by TGF-β1 in Renal Tubular Epithelial NRK-52E Cells via Inhibiting Egr-1

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Meiping Guan ◽  
Wenqi Li ◽  
Lingling Xu ◽  
Yanmei Zeng ◽  
Dan Wang ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mesenchymal Transition ◽  
Early Growth Response ◽  
Real Time Quantitative Pcr ◽  
Novel Target ◽  
Renal Tubular ◽  
Tgf Β1 ◽  
E Cadherin

The early growth response- (Egr-) 1 has been found to play a key role in organ fibrosis. Metformin has been shown to be effective in attenuating renal tubular epithelial-to-mesenchymal transition (EMT), which is involved in renal fibrosis. However, it is unknown whether metformin improves EMT via inhibiting Egr-1. In this study, rat renal tubular epithelial (NRK-52 E) cells, treated by transforming growth factor- (TGF-)β1 of 10 ng/ml with or without metformin of 1 mmol/l, were transfected by siEgr-1 or M61-Egr-1 plasmids to knock down or overexpress Egr-1, respectively. The gene and protein expressions of E-cadherin,α-SMA, fibronectin (FN), and Egr-1 were determined by real-time quantitative PCR and Western blotting, respectively. We observed that TGF-β1 significantly reduced E-cadherin expression and upregulated the expressions of FN,α-SMA, and Egr-1, which can be reversed by metformin. M61-Egr-1 transfection could exacerbate EMT, which can be reversed by metformin. Taken together, our data show that Egr-1 plays an important role in TGF-β1-induced EMT of renal tubular epithelial cells and metformin improves EMT while inhibiting Egr-1, which provides a potential novel target to combat renal fibrosis.

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