scholarly journals P1196AN INIHIBITOR OF KRUPPEL-LIKE FACTOR 5 SUPPRESSES PERITONEAL FIBROSIS IN MICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Kumiko Muta ◽  
Yuka Nakazawa ◽  
Yoko Obata ◽  
Hiro Inoue ◽  
Kenta Torigoe ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Retinoic Acid Receptor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Peritoneal Fibrosis ◽  
Retinoic Acid Receptor Α ◽  
Klf5 Expression

Abstract Background and Aims We presented previously that Am80, a synthetic retinoic acid receptor α specific agonist, inhibited the expression of Krüppel-like transcription factor 5 (KLF5) and reduced peritoneal fibrosis in mice. Now, we examined further detail about the mechanism to inhibit peritoneal fibrosis. Method Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) into peritoneal cavity of ICR mice. Am80 was administered orally for every day from the start of CG injection. After 3 weeks of treatment, peritoneal tissues were examined using serial sections by immunohistochemistry to identify what kind of cells expressed KLF5. We also examined the effect of Am80 to inhibit peritoneal fibrosis in vitro. Results While KLF5 was expressed in the thickened submesothelial area of CG injected mice, Am80 treatment reduced KLF5 expression and remarkably attenuated peritoneal thickening. The numbers of transforming growth factor β positive cells, α-smooth muscle actin (αSMA) or F4/80 positive cells were significantly decreased in Am80 treated group. KLF5 was expressed in αSMA, F4/80 or CD31 positive cells. Conclusion These results indicate the KLF5 might not only associate phenotypical differentiation from fibroblasts to myofibroblasts but also regulate inflammatory responses and angiogenesis in peritoneal fibrosis model. Am80 can suppress peritoneal fibrosis through inhibiting these mechanisms. In vitro experiments are ongoing.

An inhibitor of Krüppel-like factor 5 suppresses peritoneal fibrosis in mice

2021 ◽  
pp. 089686082098132
Author(s):  
Kumiko Muta ◽  
Yuka Nakazawa ◽  
Yoko Obata ◽  
Hiro Inoue ◽  
Kenta Torigoe ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transforming Growth Factor ◽  
Retinoic Acid Receptor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Type Iii Collagen ◽  
Peritoneal Fibrosis ◽  
Peritoneal Tissue ◽  
Klf5 Expression

Back ground: Krüppel-like transcription factor 5 (KLF5) is a transcription factor regulating cell proliferation, angiogenesis and differentiation. It has been recently reported that Am80, a synthetic retinoic acid receptor α-specific agonist, inhibits the expression of KLF5. In the present study, we have examined the expression of KLF5 in fibrotic peritoneum induced by chlorhexidine gluconate (CG) in mouse and evaluated that Am80, as an inhibitor of KLF5, can reduce peritoneal fibrosis. Methods: Peritoneal fibrosis was induced by intraperitoneal injection of CG into peritoneal cavity of ICR mice. Am80 was administered orally for every day from the start of CG injection. Control mice received only a vehicle (0.5% carboxymethylcellulose solution). After 3 weeks of treatment, peritoneal equilibration test (PET) was performed and peritoneal tissues were examined by immunohistochemistry. Results: The expression of KLF5 was less found in the peritoneal tissue of control mice, while KLF5 was expressed in the thickened submesothelial area of CG-injected mice receiving the vehicle. Am80 treatment reduced KLF5 expression and remarkably attenuated peritoneal thickening, accompanied with the reduction of type III collagen expression. The numbers of transforming growth factor β-positive cells, α-smooth muscle actin-positive cells and infiltrating macrophages were significantly decreased in Am80-treated group. PET revealed the increased peritoneal permeability in CG mice, whereas Am80 administration significantly improved the peritoneal high permeability state. Conclusions: These results indicate the involvement of KLF5 in the progression of experimental peritoneal fibrosis and suggest that Am80 may be potentially useful for the prevention of peritoneal fibrosis through inhibition of KLF5 expression.

scholarly journals Type of MRI contrast, tissue gadolinium, and fibrosis

2014 ◽  
Vol 307 (7) ◽  
pp. F844-F855 ◽  
Author(s):  
Catherine Do ◽  
Jeffrey L. Barnes ◽  
Chunyan Tan ◽  
Brent Wagner
Keyword(s):  
Contrast Agents ◽  
Nephrogenic Systemic Fibrosis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Mri Contrast ◽  
Cultured Fibroblasts ◽  
Low K

It has been presupposed that the thermodynamic stability constant ( Ktherm) of gadolinium-based MRI chelates relate to the risk of precipitating nephrogenic systemic fibrosis. The present study compared low- Ktherm gadodiamide with high- Ktherm gadoteridol in cultured fibroblasts and rats with uninephrectomies. Gadolinium content was assessed using scanning electron microscopy equipped with energy-dispersive X-ray spectroscopy in paraffin-embedded tissues. In vitro, fibroblasts demonstrated dose-dependent fibronectin generation, transforming growth factor-β production, and expression of activated myofibroblast stress fiber protein α-smooth muscle actin. There were negligible differences with respect to toxicity or proliferation between the two contrast agents. In the rodent model, gadodiamide treatment led to greater skin fibrosis and dermal cellularity than gadoteridol. In the kidney, both contrast agents led to proximal tubule vacuolization and increased fibronectin accumulation. Despite large detectable gadolinium signals in the spleen, skin, muscle, and liver from the gadodiamide-treated group, contrast-induced fibrosis appeared to be limited to the skin and kidney. These findings support the hypothesis that low- Ktherm chelates have a greater propensity to elicit nephrogenic systemic fibrosis and demonstrate that certain tissues are resistant to these effects.

P1226MITOCHONIC ACID 5 (MA-5) AMELIORATES CG-INDUCED PERITONEAL FIBROSIS IN MICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Hiro Inoue ◽  
Yoko Obata ◽  
Takehiro Suzuki ◽  
Miki Torigoe ◽  
Kenta Torigoe ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mitochondrial Dysfunction ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Parietal Peritoneum ◽  
Disease Models ◽  
Peritoneal Fibrosis ◽  
Chemotactic Protein

Abstract Background and Aims Peritoneal fibrosis is one of important complications induced by long-term peritoneal dialysis. Mitochondrial dysfunction causes an increase of oxidative stress and depletion of ATP. Thus, it may be associated with a variety of disease including fibrosis in several organs. Recently, mitochonic acid 5 (MA-5) was synthesized and its therapeutic potential for mitochondrial dysfunction in kidney disease models has been reported. In this study, we investigated the effect of MA-5 for peritoneal fibrosis model in mice. Method Peritoneal fibrosis was induced by intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 3 weeks in C57/BL6 mice. MA-5 was administered at 2 mg/kg by gavage every day from the initiation of CG injection. Control mice received only a vehicle (distilled water). After 3 weeks of treatment, the animals were sacrificed and the peritoneal tissues were collected. The peritoneal sections were stained with Masson’s trichrome for light microscopic examination and the fibrotic thickening of parietal peritoneum was measured on the randomly selected different regions on each section. The expressions of F4/80, which is a marker of macrophages, monocyte chemotactic protein 1 (MCP1), α-smooth muscle actin (α-SMA), and transforming growth factor-β (TGF-β) were evaluated by immunohistochemistry. Results The fibrotic thickening of parietal peritoneum was significantly attenuated in MA-5 treated mice compared with control mice (the thickness of submesothelial area: 100.24 +/- 13.67 vs 54.78 +/- 7.43 μm (p<0.05)). The numbers of TGF-β positive cells, α-SMA positive cells, MCP1 positive cells and infiltrating macrophages were significantly decreased in MA-5 treated mice than those in control mice. Conclusion These results suggest that MA-5 may have a therapeutic potential in the progression of peritoneal fibrosis as well as kidney disease models.

TGF-β1 is a negative regulator of lymphatic regeneration during wound repair

2008 ◽  
Vol 295 (5) ◽  
pp. H2113-H2127 ◽  
Author(s):  
Nicholas W. Clavin ◽  
Tomer Avraham ◽  
John Fernandez ◽  
Sanjay V. Daluvoy ◽  
Marc A. Soares ◽  
...  
Keyword(s):  
Wound Repair ◽  
Cellular Proliferation ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Significant Risk ◽  
Collagen Gel ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Tubule Formation

Although clinical studies have identified scarring/fibrosis as significant risk factors for lymphedema, the mechanisms by which lymphatic repair is impaired remain unknown. Transforming growth factor -β1 (TGF-β1) is a critical regulator of tissue fibrosis/scarring and may therefore also play a role in the regulation of lymphatic regeneration. The purpose of this study was therefore to assess the role of TGF-β1 on scarring/fibrosis and lymphatic regeneration in a mouse tail model. Acute lymphedema was induced in mouse tails by full-thickness skin excision and lymphatic ligation. TGF-β1 expression and scarring were modulated by repairing the wounds with or without a topical collagen gel. Lymphatic function and histological analyses were performed at various time points. Finally, the effects of TGF-β1 on lymphatic endothelial cells (LECs) in vitro were evaluated. As a result, the wound repair with collagen gel significantly reduced the expression of TGF-β1, decreased scarring/fibrosis, and significantly accelerated lymphatic regeneration. The addition of recombinant TGF-β1 to the collagen gel negated these effects. The improved lymphatic regeneration secondary to TGF-β1 inhibition was associated with increased infiltration and proliferation of LECs and macrophages. TGF-β1 caused a dose-dependent significant decrease in cellular proliferation and tubule formation of isolated LECs without changes in the expression of VEGF-C/D. Finally, the increased expression of TGF-β1 during wound repair resulted in lymphatic fibrosis and the coexpression of α-smooth muscle actin and lymphatic vessel endothelial receptor-1 in regenerated lymphatics. In conclusion, the inhibition of TGF-β1 expression significantly accelerates lymphatic regeneration during wound healing. An increased TGF-β1 expression inhibits LEC proliferation and function and promotes lymphatic fibrosis. These findings imply that the clinical interventions that diminish TGF-β1 expression may be useful in promoting more rapid lymphatic regeneration.

Antagonistic Effects of Insulin and TGF-β3 during Chondrogenic Differentiation of Human BMSCs under a Minimal Amount of Factors

2016 ◽  
Vol 201 (2) ◽  
pp. 88-96 ◽  
Author(s):  
Emilio Satoshi Hara ◽  
Mitsuaki Ono ◽  
Yuya Yoshioka ◽  
Junji Ueda ◽  
Yuri Hazehara ◽  
...  
Keyword(s):  
Chondrogenic Differentiation ◽  
Transforming Growth Factor ◽  
Direct Interaction ◽  
Transforming Growth Factor Β ◽  
Treated Group ◽  
Minimal Amount ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Antagonistic Effects

Growth factors are crucial regulators of cell differentiation towards tissue and organ development. Insulin and transforming growth factor-β (TGF-β) have been used as the major factors for chondrogenesis in vitro, by activating the AKT and Smad signaling pathways. Previous reports demonstrated that AKT and Smad3 have a direct interaction that results in the inhibition of TGF-β-mediated cellular responses. However, the result of this interaction between AKT and Smad3 during the chondrogenesis of human bone marrow-derived stem/progenitor cells (hBMSCs) is unknown. In this study, we performed functional analyses by inducing hBMSCs into chondrogenesis with insulin, TGF-β3 or in combination, and found that TGF-β3, when applied concomitantly with insulin, significantly decreases an insulin-induced increase in mRNA levels of the master regulator of chondrogenesis, SOX9, as well as the regulators of the 2 major chondrocyte markers, ACAN and COL2A1. Similarly, the insulin/TGF-β3-treated group presented a significant decrease in the deposition of cartilage matrix as detected by safranin O staining of histological sections of hBMSC micromass cultures when compared to the group stimulated with insulin alone. Intracellular analysis revealed that insulin-induced activation of AKT suppressed Smad3 activation in a dose-dependent manner. Accordingly, insulin/TGF-β3 significantly decreased the TGF-β3-induced increase in mRNA levels of the direct downstream factor of TGF-β/Smad3, CCN2/CGTF, compared to the group stimulated with TGF-β3 alone. On the other hand, insulin/TGF-β3 stimulation did not suppress insulin-induced expression of the downstream targets TSC2 and DDIT4/REDD1. In summary, insulin and TGF-β3 have antagonistic effects when applied concomitantly, with a minimal number of factors. The application of an insulin/TGF-β3 combination without further supplementation should be used with caution in the chondrogenic differentiation of hBMSCs.

scholarly journals Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis

2011 ◽  
Vol 208 (2) ◽  
pp. 217-225 ◽  
Author(s):  
Saskia C.A. de Jager ◽  
Beatriz Bermúdez ◽  
Ilze Bot ◽  
Rory R. Koenen ◽  
Martine Bot ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Phase ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Density Lipoprotein ◽  
Transforming Growth Factor Β ◽  
Dependent Manner ◽  
Differentiation Factor ◽  
Macrophage Chemotaxis

Growth differentiation factor (GDF) 15 is a member of the transforming growth factor β (TGF-β) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor−/− mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF-15−/− chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFβRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15−/− macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFβRII-dependent manner, a phenomenon which was not observed in G protein–coupled receptor kinase 2+/− macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2-mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFβRII-dependent inflammatory responses to vascular injury.

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

2014 ◽  
Vol 92 (5) ◽  
pp. 370-378 ◽  
Author(s):  
Stefan W. Ryter ◽  
Augustine M.K. Choi ◽  
Hong Pyo Kim
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Tyrosine Phosphatase ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Caveolin 1 ◽  
Expression Of Genes ◽  
Liver And Kidney

Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1−/−) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1−/− fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1−/− liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis.

Modulation of extracellular matrix using adenovirus vectors

2002 ◽  
Vol 30 (2) ◽  
pp. 107-111 ◽  
Author(s):  
C. D. Richards ◽  
C. Kerr ◽  
L. Tong ◽  
C. Langdon
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Transforming Growth Factor Β ◽  
Oncostatin M ◽  
Leukaemia Inhibitory Factor ◽  
Mouse Lung

Metabolism of the extracellular matrix (ECM) is a complex process that becomes disregulated in disease states characterized by chronic inflammation of joints, as is seen in rheumatoid arthritis or fibrosis of the lung. The participation of certain cytokines in this process is generally accepted (transforming growth factor-β induces fibrosis), while the roles of other cytokines are less clear. Oncostatin M (OSM) is a member of the interleukin-6/leukaemia inhibitory factor (or gp130) cytokine family, and its participation in inflammation and the regulation of ECM metabolism is supported by a number of activities identified in vitro, including regulation of matrix metallo-proteinase-1 and tissue inhibitor of metalloproteinases-1. Local overexpression of transforming growth factor-β has been shown to be fibrogenic in mouse lung, whereas local OSM over-expression via intra-articular administration has been shown to induce a pannus-like inflammatory response in the synovium of mouse knee joints. Here we examine the effects of OSM in the context of those of transforming growth factor-β using an established adenovirus vector that expresses mOSM (AdmOSM). We administered the virus intra-nasally into Balb/C mice to achieve high expression of OSM in the lung, and examined the effects at various time points. AdmOSM resulted in a vigorous inflammatory response by day 7 which was characterized by an elevation of neutrophil and mononuclear cell numbers and a marked increase in collagen deposition. These data support the use of such systems to study the ECM in vivo, and indicate a potential role for OSM in inflammatory responses that can modulate steady-state ECM deposition in Balb/C mice.

scholarly journals Nitro-oleic acid inhibits the high glucose-induced epithelial-mesenchymal transition in peritoneal mesothelial cells and attenuates peritoneal fibrosis

2020 ◽  
Vol 318 (2) ◽  
pp. F457-F467
Author(s):  
Wenyan Su ◽  
Haiping Wang ◽  
ZiYan Feng ◽  
Jing Sun
Keyword(s):  
Peritoneal Dialysis ◽  
Oleic Acid ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Muscle Actin ◽  
Peritoneal Fibrosis ◽  
Mesenchymal Transition ◽  
Peritoneal Mesothelial Cells

As an electrophilic nitroalkene fatty acid, nitro-oleic acid (OA-NO2) exerts multiple biological effects that contribute to anti-inflammation, anti-oxidative stress, and antiapoptosis. However, little is known about the role of OA-NO2 in peritoneal fibrosis. Thus, in the present study, we examined the effects of OA-NO2 on the high glucose (HG)-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMCs) and evaluated the morphological and immunohistochemical changes in a rat model of peritoneal dialysis-related peritoneal fibrosis. In in vitro experiments, we found that HG reduced the expression level of E-cadherin and increased Snail, N-cadherin, and α-smooth muscle actin expression levels in HPMCs. The above-mentioned changes were attenuated by pretreatment with OA-NO2. Additionally, OA-NO2 also inhibited HG-induced activation of the transforming growth factor-β1/Smad signaling pathway and NF-κB signaling pathway. Meanwhile, OA-NO2 inhibited HG-induced phosphorylation of Erk and JNK. The results from the in vivo experiments showed that OA-NO2 notably relieved peritoneal fibrosis by decreasing the thickness of the peritoneum; it also inhibited expression of transforming growth factor-β1, α-smooth muscle actin, N-cadherin, and vimentin and enhanced expression of E-cadherin in the peritoneum. Collectively, these results suggest that OA-NO2 inhibits the HG-induced epithelial-mesenchymal transition in HPMCs and attenuates peritoneal dialysis-related peritoneal fibrosis.

scholarly journals Nodal Facilitates Differentiation of Fibroblasts to Cancer-Associated Fibroblasts that Support Tumor Growth in Melanoma and Colorectal Cancer

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 538 ◽  
Author(s):  
Ziqian Li ◽  
Junjie Zhang ◽  
Jiawang Zhou ◽  
Linlin Lu ◽  
Hongsheng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Cancer Associated Fibroblasts ◽  
Pathway Activation

Fibroblasts become cancer-associated fibroblasts (CAFs) in the tumor microenvironment after activation by transforming growth factor-β (TGF-β) and are critically involved in cancer progression. However, it is unknown whether the TGF superfamily member Nodal, which is expressed in various tumors but not expressed in normal adult tissue, influences the fibroblast to CAF conversion. Here, we report that Nodal has a positive correlation with α-smooth muscle actin (α-SMA) in clinical melanoma and colorectal cancer (CRC) tissues. We show the Nodal converts normal fibroblasts to CAFs, together with Snail and TGF-β signaling pathway activation in fibroblasts. Activated CAFs promote cancer growth in vitro and tumor-bearing mouse models in vivo. These results demonstrate that intercellular crosstalk between cancer cells and fibroblasts is mediated by Nodal, which controls tumor growth, providing potential targets for the prevention and treatment of tumors.

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