Collagen VIII influences epithelial phenotypic changes in experimental diabetic nephropathy

2012 ◽  
Vol 303 (5) ◽  
pp. F733-F745 ◽  
Author(s):  
Ivonne Loeffler ◽  
Marita Liebisch ◽  
Gunter Wolf
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Transforming Growth Factor Β ◽  
Diabetic Mice ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Characteristic Features ◽  
Biological Methods

Epithelial-to-mesenchymal transition (EMT) is an important mechanism of renal tubulo-interstitial fibrosis in diabetic nephropathy (DN). Inducers of EMT, among others, are transforming growth factor-β1(TGF-β1) as well as extracellular collagens. In renal cells of diabetic mice and in kidneys of patients with DN, the expression of collagen VIII (gene: Col8α1/α2) is enhanced and characteristic features of DN in streptozotocin (STZ)-induced diabetic Col8α1/α2 knockout-(KO) mice are attenuated compared with diabetic wild-type mice. This study aimed to investigate whether collagen type VIII may influence the induction of EMT. DN was induced in wild-type and Col8α1/α2-KO mice using the established and widely accepted low-dose STZ model [treatment for 5 consecutive days (50 mg/kg)]. Healthy and diabetic mice were analyzed for changes in renal function and the expression of EMT-related genes and proteins. Renal morphology, fibrosis, and various EMT markers were studied in kidneys using immunohistological and molecular biological methods. Knockout of Col8α1/α2 attenuated albuminuria, extracellular matrix production, as well as fibrosis. Furthermore, the kidneys of diabetic Col8α1/α2-KO mice showed a marked reduction in interstitial myofibroblasts, and in tubular cells the inhibition of the expression of epithelial markers as well as the expression of typical mesenchymal markers was reduced. The present study demonstrates that in contrast to diabetic wild-type mice EMT-like changes were attenuated in diabetic Col8α1/α2-KO mice, which indicates that either collagen VIII may be one of the major inducers of EMT-like changes in kidneys of diabetic wild-type mice or/possibly the lack of Col8α1/α2 disrupts TGF-β1-induced EMT-like changes.

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

The molecular mediators of type 2 epithelial to mesenchymal transition (EMT) and their role in renal pathophysiology

2010 ◽  
Vol 12 ◽  
Author(s):  
Wendy C. Burns ◽  
Merlin C. Thomas
Keyword(s):  
Kidney Disease ◽  
Transcriptional Activation ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Cell Contact ◽  
Mesenchymal Transition ◽  
Tubular Cells

Common to all forms of chronic kidney disease is the progressive scarring of the tubulo-interstitial space, associated with the acquisition and accumulation of activated myofibroblasts. Many of these myofibroblasts are generated when tubular epithelial cells progressively lose their epithelial characteristics (cell–cell contact, microvilli, tight-junction proteins, apical–basal polarity) and acquire features of a mesenchymal lineage, including stress fibres, filopodia and augmented matrix synthesis. This process, known as epithelial to mesenchymal transition (EMT), plays an important role in progressive kidney disease. For EMT to occur in tubular cells, the transcriptional activation (and derepression) of genes required to sustain mesenchymal-type structures and functions (e.g. vimentin, α-smooth muscle actin) must occur alongside repression (or deactivation) of genes that act to maintain the epithelial phenotype (e.g. E-cadherin, bone morphogenic protein 7). Several factors have been suggested as potential initiators of EMT. With a few key exceptions, these triggers require the induction of transforming growth factor β (TGF-β) and downstream mediators, including SMADs, CTGF, ILK and SNAI1. Activation of TGF-β receptors is also able to stimulate a range of additional pathways (so-called non-SMAD activation), including RhoA, mitogen-activated protein kinase and phosphoinositide 3-kinase signalling cascades, that also contribute to EMT and renal fibrogenesis. This review examines in detail the molecular mediators of EMT in tubular cells and its potential role as a long-lasting mediator of metabolic stress.

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 Epigenetic Reprogramming of TGF-β Signaling in Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 726 ◽  
Author(s):  
Sudha Suriyamurthy ◽  
David Baker ◽  
Peter ten Dijke ◽  
Prasanna Vasudevan Iyengar
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Mechanisms ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Selective Targeting

The Transforming Growth Factor-β (TGF-β) signaling pathway has a well-documented, context-dependent role in breast cancer development. In normal and premalignant cells, it acts as a tumor suppressor. By contrast, during the malignant phases of breast cancer progression, the TGF-β signaling pathway elicits tumor promoting effects particularly by driving the epithelial to mesenchymal transition (EMT), which enhances tumor cell migration, invasion and ultimately metastasis to distant organs. The molecular and cellular mechanisms that govern this dual capacity are being uncovered at multiple molecular levels. This review will focus on recent advances relating to how epigenetic changes such as acetylation and methylation control the outcome of TGF-β signaling and alter the fate of breast cancer cells. In addition, we will highlight how this knowledge can be further exploited to curb tumorigenesis by selective targeting of the TGF-β signaling pathway.

scholarly journals Transforming Growth Factor β/NR4A1-Inducible Breast Cancer Cell Migration and Epithelial-to-Mesenchymal Transition Is p38α (Mitogen-Activated Protein Kinase 14) Dependent

2017 ◽  
Vol 37 (18) ◽  
Author(s):  
Erik Hedrick ◽  
Stephen Safe
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Growth Factor ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein

ABSTRACT Transforming growth factor β (TGF-β)-induced migration of triple-negative breast cancer (TNBC) cells is dependent on nuclear export of the orphan receptor NR4A1, which plays a role in proteasome-dependent degradation of SMAD7. In this study, we show that TGF-β induces p38α (mitogen-activated protein kinase 14 [MAPK14]), which in turn phosphorylates NR4A1, resulting in nuclear export of the receptor. TGF-β/p38α and NR4A1 also play essential roles in the induction of epithelial-to-mesenchymal transition (EMT) and induction of β-catenin in TNBC cells, and these TGF-β-induced responses and nuclear export of NR4A1 are blocked by NR4A1 antagonists, the p38 inhibitor SB202190, and kinase-dead [p38(KD)] and dominant-negative [p38(DN)] forms of p38α. Inhibition of NR4A1 nuclear export results in nuclear export of TGF-β-induced β-catenin, which then undergoes proteasome-dependent degradation. TGF-β-induced β-catenin also regulates NR4A1 expression through formation of the β-catenin–TCF-3/TCF-4/LEF-1 complex on the NR4A1 promoter. Thus, TGF-β-induced nuclear export of NR4A1 in TNBC cells plays an essential role in cell migration, SMAD7 degradation, EMT, and induction of β-catenin, and all of these pathways are inhibited by bis-indole-derived NR4A1 antagonists that inhibit nuclear export of the receptor and thereby block TGF-β-induced migration and EMT.

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