scholarly journals Regulation of Renal Fibrosis by Macrophage Polarization

2015 ◽  
Vol 35 (3) ◽  
pp. 1062-1069 ◽  
Author(s):  
Bixia Pan ◽  
Guohui Liu ◽  
Zongpei Jiang ◽  
Dongwen Zheng
Keyword(s):  
Renal Injury ◽  
Renal Fibrosis ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Macrophage Polarization ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
M2 Macrophages ◽  
Mesenchymal Transition

Background/Aims: Since renal fibrosis always predisposes end-stage renal disease, elucidation of the molecular mechanisms that underlie the progression of renal fibrosis may substantially improve the understanding and treatment for renal failure. Previous studies have highlighted an important counteraction between transforming growth factor β 1 (TGFβ1) and bone morphogenic protein 7 (BMP7) in the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells during chronic renal injury. Macrophages are also believed to play a critical role in renal fibrosis. However, the relationship between macrophages and EMT is unknown. Methods: Here, we used a mouse unilateral ureteral obstruction (UUO) model to address to these questions, and analyzed macrophage and its subpopulations purified by flow cytometry. Results: We found that the recruited macrophages are polarized to a M2 subtype after renal injury. M2 macrophages released high levels TGFβ1 to suppress BMP7 to enhance EMT-induced renal fibrosis. Depletion of M2 macrophages, but not of M1 macrophages, specifically inhibited EMT, and subsequently the renal fibrosis. Adoptive transplantation of M2 macrophages deteriorated renal fibrosis. Conclusion: Thus, our study highlights M2 macrophages as a critical target for treating renal fibrosis.

scholarly journals Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 183
Author(s):  
Akshita B. Bhatt ◽  
Saloni Patel ◽  
Margarite D. Matossian ◽  
Deniz A. Ucar ◽  
Lucio Miele ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.

scholarly journals The Epithelial-to-Mesenchymal Transition (EMT) in the Development and Metastasis of Malignant Pleural Mesothelioma

2021 ◽  
Vol 22 (22) ◽  
pp. 12216
Author(s):  
Valeria Ramundo ◽  
Giada Zanirato ◽  
Elisabetta Aldieri
Keyword(s):  
Oxidative Stress ◽  
Malignant Pleural Mesothelioma ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Asbestos Exposure ◽  
Transforming Growth Factor Β ◽  
Pleural Mesothelioma ◽  
Mesenchymal Transition ◽  
Pharmacological Approach

Malignant pleural mesothelioma (MPM) is an aggressive tumor mainly associated with asbestos exposure and is characterized by a very difficult pharmacological approach. One of the molecular mechanisms associated with cancer onset and invasiveness is the epithelial-to-mesenchymal transition (EMT), an event induced by different types of inducers, such as transforming growth factor β (TGFβ), the main inducer of EMT, and oxidative stress. MPM development and metastasis have been correlated to EMT; On one hand, EMT mediates the effects exerted by asbestos fibers in the mesothelium, particularly via increased oxidative stress and TGFβ levels evoked by asbestos exposure, thus promoting a malignant phenotype, and on the other hand, MPM acquires invasiveness via the EMT event, as shown by an upregulation of mesenchymal markers or, although indirectly, some miRNAs or non-coding RNAs, all demonstrated to be involved in cancer onset and metastasis. This review aims to better describe how EMT is involved in driving the development and invasiveness of MPM, in an attempt to open new scenarios that are useful in the identification of predictive markers and to improve the pharmacological approach against this aggressive cancer.

scholarly journals The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs

2006 ◽  
Vol 13 (2) ◽  
pp. 379-400 ◽  
Author(s):  
Markus C Fleisch ◽  
Christopher A Maxwell ◽  
Mary-Helen Barcellos-Hoff
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Therapeutic Interventions ◽  
Mesenchymal Transition ◽  
Endocrine Organs ◽  
Β Function

Transforming growth factor β (TGF-β) is a ubiquitous cytokine that plays a critical role in numerous pathways regulating cellular and tissue homeostasis. TGF-β is regulated by hormones and is a primary mediator of hormone response in uterus, prostate and mammary glands. This review will address the role of TGF-β in regulating hormone-dependent proliferation and morphogenesis. The subversion of TGF-β regulation during the processes of carcinogenesis, with particular emphasis on its effects on genetic stability and epithelial to mesenchymal transition, will also be examined. An understanding of the multiple and complex mechanisms of TGF-β regulation of epithelial function, and the ultimate loss of TGF-β function during carcinogenesis, will be critical in the design of novel therapeutic interventions for endocrine-related cancers.

scholarly journals Metastasis: new functional implications of platelets and megakaryocytes

Blood ◽  
2016 ◽  
Vol 128 (1) ◽  
pp. 24-31 ◽  
Author(s):  
Raphael Leblanc ◽  
Olivier Peyruchaud
Keyword(s):  
Bone Marrow ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Skeletal Metastasis ◽  
Transforming Growth Factor Β ◽  
High Bone Mass ◽  
Mesenchymal Transition ◽  
Essential Components

Abstract Platelets are essential components of hemostasis. Due to a plethora of factors released on activation, platelet functions are also connected to tumor growth, notably by acting on angiogenesis. It is now well recognized that major roles of platelets in the poor outcome of cancer patients occurs during hematogenous dissemination of cancer cells. In this review, we describe recent insights into the molecular mechanisms supporting the prometastatic activity of platelets. Platelets have been shown to promote survival of circulating tumor cells (CTCs) in the bloodstream by conferring resistance to the shear stress and attack from natural killer cells. Recently, platelets were found to promote and/or maintain the state of epithelial to mesenchymal transition on CTCs through platelet secretion of transforming growth factor β in response to CTC activation. At a later stage in the metastatic process, platelets promote extravasation and establishment of metastatic cells in distant organs as observed in bone. This particular environment is also the site of hematopoiesis, megakaryocytopoiesis, and platelet production. Increasing the number of megakaryocytes (MKs) in the bone marrow results in a high bone mass phenotype and inhibits skeletal metastasis formation of prostate cancer cells. As a result of their specific location in vascular niches in the bone marrow, MK activity might contribute to the “seed and soil” suitability between CTCs and bone. In conclusion, recent findings have made a great advance in our knowledge on how platelets contribute to the metastatic dissemination of cancer cells and that may support the development of new antimetastasis therapies.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

scholarly journals Noncoding RNAs as Promising Diagnostic Biomarkers and Therapeutic Targets in Intestinal Fibrosis of Crohn’s Disease: The Path From Bench to Bedside

2020 ◽  
Author(s):  
Long-Yuan Zhou ◽  
Si-Nan Lin ◽  
Florian Rieder ◽  
Min-Hu Chen ◽  
Sheng-Hong Zhang ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Noncoding Rnas ◽  
Transforming Growth Factor Β ◽  
Circular Rnas ◽  
Diagnostic Biomarkers ◽  
Mesenchymal Transition ◽  
Intestinal Fibrosis ◽  
Fibrotic Diseases ◽  
Endothelial To Mesenchymal Transition

Abstract Fibrosis is a major pathway to organ injury and failure, accounting for more than one-third of deaths worldwide. Intestinal fibrosis causes irreversible and serious clinical complications, such as strictures and obstruction, secondary to a complex pathogenesis. Under the stimulation of profibrotic soluble factors, excessive activation of mesenchymal cells causes extracellular matrix deposition via canonical transforming growth factor-β/Smads signaling or other pathways (eg, epithelial-to-mesenchymal transition and endothelial-to-mesenchymal transition) in intestinal fibrogenesis. In recent studies, the importance of noncoding RNAs (ncRNAs) stands out in fibrotic diseases in that ncRNAs exhibit a remarkable variety of biological functions in modulating the aforementioned fibrogenic responses. In this review, we summarize the role of ncRNAs, including the emerging long ncRNAs and circular RNAs, in intestinal fibrogenesis. Notably, the translational potential of ncRNAs as diagnostic biomarkers and therapeutic targets in the management of intestinal fibrosis is discussed based on clinical trials from fibrotic diseases in other organs. The main points of this review include the following: • Characteristics of ncRNAs and mechanisms of intestinal fibrogenesis • Wide participation of ncRNAs (especially the emerging long ncRNAs and circular RNAs) in intestinal fibrosis, including transforming growth factor-β signaling, epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition, and extracellular matrix remodeling • Translational potential of ncRNAs in the diagnosis and treatment of intestinal fibrosis based on clinical trials from fibrotic diseases in other organs

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.

scholarly journals Role of Stat3 Signaling in Control of EMT of Tubular Epithelial Cells During Renal Fibrosis

2017 ◽  
Vol 42 (6) ◽  
pp. 2552-2558 ◽  
Author(s):  
Jingsong Liu ◽  
Ying Zhong ◽  
Guoyong Liu ◽  
Xiaobai Zhang ◽  
Bofei Xiao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Renal Injury ◽  
Renal Fibrosis ◽  
Critical Role ◽  
Dependent Manner ◽  
Tubular Epithelial Cells ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Phosphorylated Stat3

Background/Aims: Transforming growth factor β 1 (TGFβ1) plays a critical role in the epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells (TECs) during renal injury, a major cause of acute renal failure, renal fibrosis and obstructive nephropathy. However, the underlying molecular mechanisms remain ill-defined. Here, we addressed this question. Methods: Expression of TGFβ1, Snail, and phosphorylated Stat3 was examined by immunohistochemistry in the kidney after induction of unilateral ureteral obstruction (UUO) in mice. In vitro, primary TECs were purified by flow cytometry, and then challenged with TGFβ1 with/without presence of specific inhibitors for phosphorylation of SMAD3 or Stat3. Protein levels were determined by Western blotting. Results: We detected significant increases in Snail and phosphorylated Stat3, an activated form for Stat3, in the kidney after induction of UUO in mice. In vitro, TGFβ1-challenged primary TECs upregulated Snail, in a SMAD3/Stat3 dependent manner. Conclusion: Our study sheds light on the mechanism underlying the EMT of TECs after renal injury, and suggests Stat3 signaling as a promising innovative therapeutic target for prevention of renal fibrosis.

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.

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