Journal articles on the topic 'Collagen Type 1 CTGF'
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1
Takeuchi, H., S. Kubota, E. Murakashi, Y. Zhou, K. Endo, P. S. Ng, M. Takigawa, and Y. Numabe. "Nicotine-induced CCN2: from Smoking to Periodontal Fibrosis." Journal of Dental Research 89, no. 1 (December 4, 2009): 34–39. http://dx.doi.org/10.1177/0022034509353403.
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Since fibrosis is observed in smokers’ gingiva, it was hypothesized that fibrosis was caused by nicotine in the periodontium. Therefore, in this study, we investigated the effects of nicotine on the induction of a profibrotic molecule, connective tissue growth factor (CCN2/CTGF), in human gingival fibroblasts (HGFs) and periodontal ligament (PDL) cells. With 1 μg/mL nicotine, vacuolization and attenuated proliferation were observed. Interestingly, 1 μg/mL nicotine increased the production of CCN2/CTGF protein in both cells without increasing mRNA expression. Furthermore, type I collagen mRNA and protein were also increased and were significantly blocked by a CCN2/CTGF neutralizing antibody. This is the first report to describe a relationship between nicotine and CCN2/CTGF in periodontal tissue cells. Analysis of our data also indicated that nicotine was cytotoxic, while it increased CCN2/CTGF and, eventually, type I collagen production. These findings suggest that periodontal fibrosis can be promoted by nicotine from smoking via effects on CCN2/CTGF.
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Romero, Jose R., Dennis A. Ricupero, Alicia Rivera, Ronald H. Goldstein, and Paul R. Conlin. "Activation of Na + /Ca 2+ Exchanger in Kinin B 1 Receptor-Stimulated Human Fibroblast Is Associated with Collagen Production." Hypertension 36, suppl_1 (October 2000): 710–20. http://dx.doi.org/10.1161/hyp.36.suppl_1.710.
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P148 The arterial wall in hypertension is characterized by thickening of the media, in part due to increased deposition of connective tissue. Autocrine and paracrine factors may participate in this process; including products of the kallikrein-kinin system. We evaluated early signal transduction events and effects on collagen formation in B 1 -stimulated human myofibroblast cells (IMR-90). We measured cytosolic calcium (Ca cyt ) levels in cells loaded with FURA-2AM. Gene expression of connective tissue growth factor (CTGF) and α1(I) collagen was determined by estimating mRNA levels using Northern analysis of B 1 stimulated cells. Activation of the B 1 receptor with des-arg 10 -kallidin stimulated a three-fold increase in CTGF mRNA by increasing its stability. Furthermore, B 1 receptor activation caused an increase in α1(I) collagen mRNA and a four-fold increase in type I collagen synthesis in these cells; events not observed in B 2 receptor-stimulated cells. Activation of the B 1 receptor stimulated a dose dependent rise in Ca cyt (EC 50 =1.9nM) which was completely inhibited by des-arg 10 -[leu 9 ]-kallidin (100nM), a B 1 receptor antagonist. Isosmotic replacement of extracellular Na + with N -methyl,D-glucamine blocked > 90% of the B 1 stimulated rise in Ca cyt . A similar effect was observed when Ca 2+ was removed from the extracellular media, suggesting a role for the plasma membrane Na + /Ca 2+ exchanger (NCX). To further define a role for the NCX on CTGF formation we used dichlorobenzamil (DCB) and KB-R7943, two specific NCX inhibitors. DCB completely blocked the activation of B 1 receptor induced increase in CTGF mRNA stability while not affecting basal CTGF mRNA levels. In contrast, preincubation with EIPA, an amiloride analog, did not affect basal or stimulated CTGF mRNA levels. Furthermore, 60μM KB-R7943 blocked the B 1 stimulated rise in Ca cyt . NCX isoform 1 was identified in these cells using RT-PCR and immuno-detection. Thus, B 1 receptor stimulation increases fibrogenesis through a mechanism that involves modulation of cation metabolism via reverse-mode activation of NCX.
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Chen, Chung-Ming, Hsiu-Chu Chou, Leng-Fang Wang, and Yaw-Dong Lang. "Experimental Oligohydramnios Decreases Collagen in Hypoplastic Fetal Rat Lungs." Experimental Biology and Medicine 233, no. 11 (November 2008): 1334–40. http://dx.doi.org/10.3181/0803-rm-99.
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Neonates with premature rupture of the membrane and oligohydramnios have an increased risk of acute respiratory morbidity. The aims of this study are to investigate the effects of experimental oligohydramnios on transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF) expressions and collagen level in fetal rat lungs. On day 16 of gestation, we anesthetized timed pregnant Sprague-Dawley dams, punctured the uterine wall and fetal membranes of each amniotic sac which resulted in oligohydramnios. Fetuses in the opposite uterine horn served as controls. On days 19 and 21 of gestation, fetuses were delivered by cesarean section. Rats exposed to oligohydramnios exhibited significantly lower lung weight/body weight ratios on days 19 and 21 of gestation than did the control rats. Lung type I collagen and TGF-β1 mRNA expressions and lung collagen levels were significantly decreased in rats exposed to oligohydramnios on days 19 and 21 of gestation. Type I collagen and inhibitors of metalloproteinase-1 (TIMP-1) proteins were decreased and matrix metalloproteinase-1 (MMP-1) was increased in oligohydramnios-exposed rats on days 19 and 21 of gestation. CTGF mRNA expressions were comparable between control and oligohydramnios-exposed rats on days 19 and 21 of gestation. These data suggest that downregulation of collagen might be involved in the pathogenesis of oligohydramnios-induced respiratory morbidity.
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Wang, Shinong, and Raimund Hirschberg. "BMP7 antagonizes TGF-β-dependent fibrogenesis in mesangial cells." American Journal of Physiology-Renal Physiology 284, no. 5 (May 1, 2003): F1006—F1013. http://dx.doi.org/10.1152/ajprenal.00382.2002.
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Exogenous administration of recombinant human bone morphogenetic protein (BMP)-7 was recently shown to ameliorate renal glomerular and interstitial fibrosis in rodents with experimental renal diseases. We tested the hypothesis that BMP7 functions by antagonizing profibrogenic events that are induced by transforming growth factor (TGF)-β in cultured mesangial cells. Incubation of murine mesangial cells with TGF-β (50–200 pM) increased cell-associated collagen type IV and fibronectin, soluble collagen type IV, thrombospondin, and connective tissue growth factor (CTGF). Coincubation with recombinant human BMP7 (200 pM) reduced the increase of these ECM proteins and CTGF. The changes in collagen type IV and fibronectin proteins occurred without concomitant changes in collagen type α1IV and fibronectin mRNA levels, suggesting that TGF-β and BMP7 act primarily by affecting ECM protein degradation. Indeed, TGF-β decreases the levels and activity of matrix metalloprotease (MMP)-2, the major metalloprotease that is secreted by mesangial cells. Moreover, BMP7 inhibits TGF-β-induced activation of MMP2. Because TGF-β reduces the activity of MMPs through increasing plasminogen activator inhibitor (PAI)-1, we tested whether BMP7 interferes with this TGF-β effect. BMP7 reduces, by about two-thirds, the activation of a PAI-1 promoter/luciferase reporter in cells stably transfected with this construct. The findings from these studies indicate that BMP7 reduces TGF-β-induced ECM protein accumulation in cultured mesangial cells primarily by maintaining levels and activity of MMP2 partially through prevention of TGF-β-dependent upregulation of PAI-1.
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Hillege, Michèle, Ricardo Galli Caro, Carla Offringa, Gerard de Wit, Richard Jaspers, and Willem Hoogaars. "TGF-β Regulates Collagen Type I Expression in Myoblasts and Myotubes via Transient Ctgf and Fgf-2 Expression." Cells 9, no. 2 (February 6, 2020): 375. http://dx.doi.org/10.3390/cells9020375.
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Transforming Growth Factor β (TGF-β) is involved in fibrosis as well as the regulation of muscle mass, and contributes to the progressive pathology of muscle wasting disorders. However, little is known regarding the time-dependent signalling of TGF-β in myoblasts and myotubes, as well as how TGF-β affects collagen type I expression and the phenotypes of these cells. Here, we assessed effects of TGF-β on gene expression in C2C12 myoblasts and myotubes after 1, 3, 9, 24 and 48 h treatment. In myoblasts, various myogenic genes were repressed after 9, 24 and 48 h, while in myotubes only a reduction in Myh3 expression was observed. In both myoblasts and myotubes, TGF-β acutely induced the expression of a subset of genes involved in fibrosis, such as Ctgf and Fgf-2, which was subsequently followed by increased expression of Col1a1. Knockdown of Ctgf and Fgf-2 resulted in a lower Col1a1 expression level. Furthermore, the effects of TGF-β on myogenic and fibrotic gene expression were more pronounced than those of myostatin, and knockdown of TGF-β type I receptor Tgfbr1, but not receptor Acvr1b, resulted in a reduction in Ctgf and Col1a1 expression. These results indicate that, during muscle regeneration, TGF-β induces fibrosis via Tgfbr1 by stimulating the autocrine signalling of Ctgf and Fgf-2.
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Chaqour, Brahim, Catherine Whitbeck, Ji-Soo Han, Edward Macarak, Pat Horan, Paul Chichester, and Robert Levin. "Cyr61 and CTGF are molecular markers of bladder wall remodeling after outlet obstruction." American Journal of Physiology-Endocrinology and Metabolism 283, no. 4 (October 1, 2002): E765—E774. http://dx.doi.org/10.1152/ajpendo.00131.2002.
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Cysteine-rich protein (Cyr61) and connective tissue growth factor (CTGF) are key immediate early growth factors with functions in cell proliferation, differentiation, and extracellular matrix synthesis. Studies were performed to assess the gene expression profile of Cyr61 and CTGF in rat urinary bladder during growth in response to partial outlet obstruction. The mRNA levels of Cyr61 as determined by ribonuclease protection assay increased sharply after 1 day and remained elevated throughout the time period of the obstruction. This correlates well with increased bladder weight. The CTGF mRNA levels seemed to peak within the second week of the urethral obstruction and correlate well with increased type I collagen mRNA. The expression pattern of either Cyr61 or CTGF proteins corroborated that of their respective mRNAs. Immunohistochemical analyses showed that immunoreactivity of Cyr61 was confined to detrusor smooth muscle and that of CTGF was detected within both detrusor muscle and lamina propria layers. These data strongly indicate the involvement of Cyr61 and CTGF in bladder wall remodeling as a result of the outlet obstruction.
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Zhang, Lin, Jin Tan, Yi-Ping Liu, Xun Liu, and Mang Luo. "Curcumin relieves the arecoline-induced fibrosis of oral mucosal fibroblasts via inhibiting HIF-1α/TGF-β/CTGF signaling pathway: an in vitro study." Toxicology Research 10, no. 3 (May 2021): 631–38. http://dx.doi.org/10.1093/toxres/tfab046.
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Abstract Oral submacosal fibrosis (OSF) has been recognized as one of the oral potentially malignant disorders. Areca nut chewing is implicated in this pathological fibrosis. The current treatments for OSF have failed to achieve the desired curative effect. Here, we propose that curcumin has excellent therapeutic effect on OSF and explore its specific mechanism. Transwell assay was performed to detected cell migration. Flow cytometry was used to measured apoptosis. And MTT assay was performed to test cell viability. Gene and protein levels were detected by quantitative real-time polymerase chain reaction (qPCR) and western blotting. Our results displayed that curcumin treatment reduced fibrosis-related molecules (collagen type I alpha 1, collagen type III alpha 1, tissue inhibitor of metalloprotease 2) in arecoline-treated oral mucosal fibroblasts and elevated matrix metalloproteinase 2 expression. Additionally, curcumin could suppress cell proliferation and migration, and enhance the apoptosis of arecoline-treated normal oral mucosal fibroblasts. Most importantly, the hypoxia-inducible factor-1α (HIF-1α), transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) expressions in arecoline-treated normal oral mucosal fibroblasts were reduced after exposure to curcumin, whereas the activation of HIF-1α/TGF-β/CTGF axis reversed curcumin’s effect on improving fibrosis of arecoline-treated normal oral mucosal fibroblasts. Therefore, curcumin alleviated oral submucosal fibrosis via inhibiting HIF-1α/TGF-β/CTGF axis. In summary, curcumin effectively inhibited the migration and proliferation and promoted apoptosis in arecoline-induced normal oral mucosal fibroblasts by inactivating HIF-1α/TGF-β/CTGF pathway. And curcumin might be a potential therapeutic drug for OSF treatment.
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McDonald, Emily A., Ling Cheng, Blanca Jarilla, Marianne J. Sagliba, Annaliza Gonzal, Amabelle J. Amoylen, Remigio Olveda, et al. "Maternal Infection with Schistosoma japonicum Induces a Profibrotic Response in Neonates." Infection and Immunity 82, no. 1 (October 28, 2013): 350–55. http://dx.doi.org/10.1128/iai.01060-13.
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ABSTRACTThe global burden of schistosomiasis is significant, with fibrosis a major associated morbidity and the primary cause of mortality. We have previously shown that schistosomiasis during pregnancy upregulates proinflammatory cytokines in the cord blood. In this study, we extend these findings to include a large panel of fibrosis-associated markers. We developed a multiplex bead-based assay to measure the levels of 35 proteins associated with fibrosis. Cord blood from 109 neonates born to mothers residing in an area ofSchistosoma japonicumendemicity was assessed for these molecules. Ten mediators were elevated in the cord blood from schistosome-infected pregnancies, including insulin-like growth factor 1 (IGF-1), tumor growth factor β1 (TGF-β1), connective tissue growth factor (CTGF), procollagen I carboxy-terminal propeptide (PICP), amino-telopeptide of type 1 collagen (ICTP), collagen VI, desmosine, matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 1 (TIMP-1), and TIMP-4. Many of these were also positively correlated with preterm birth (PICP, ICTP, MMP-2, TGF-β1, desmosine, CTGF, TIMP-1). In addition, birth weight was 168 g lower for infants with detectable levels of CTGF than for those with CTGF levels below the level of detection. Maternal schistosomiasis results in upregulation of fibrosis-associated proteins in the cord blood of the neonate, a subset of which are also associated with adverse birth outcomes. As the first report of fibrosis-associated molecules altered in the newborn of infected mothers, this study has broad implications for the health of the fetus, stretching from gestation to adulthood.
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Roestenberg, Peggy, Frans A. van Nieuwenhoven, Jaap A. Joles, Claudia Trischberger, Paula P. Martens, Noelynn Oliver, Jan Aten, Jo W. Höppener, and Roel Goldschmeding. "Temporal expression profile and distribution pattern indicate a role of connective tissue growth factor (CTGF/CCN-2) in diabetic nephropathy in mice." American Journal of Physiology-Renal Physiology 290, no. 6 (June 2006): F1344—F1354. http://dx.doi.org/10.1152/ajprenal.00174.2005.
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Connective tissue growth factor (CTGF) is overexpressed in diabetic nephropathy (DN) and has therefore been implicated in its pathogenesis. The objective of the present study was to determine the tissue distribution of increased CTGF expression and the relationship of plasma, urinary, and renal CTGF levels to the development and severity of DN. We studied the relationship between CTGF and renal pathology in streptozotocin (STZ)-induced diabetes in C57BL/6J mice. Diabetic and age-matched control mice were killed after 1, 2, 4, and 9 wk of diabetes. In addition, key parameters of diabetes and DN were analyzed in 10-mo-old diabetic ob/ob mice and their ob/+ littermates. STZ-induced diabetic mice showed a significantly increased urinary albumin excretion after 1 wk and increased mesangial matrix score after 2 wk. Increased renal fibronectin, fibronectin ED-A, and collagen IVα1 expression, as well as elevated plasma creatinine levels, were observed after 9 wk. After 2 wk, CTGF mRNA was upregulated threefold in the renal cortex. By 9 wk, CTGF mRNA was also increased in the heart and liver. In contrast, transforming growth factor-β1 mRNA content was significantly increased only in the kidney by 9 wk. Renal CTGF expression was mainly localized in podocytes and parietal glomerular epithelial cells, and less prominent in mesangial cells. In addition, plasma CTGF levels and urinary CTGF excretion were increased in diabetic mice. Moreover, albuminuria strongly correlated with urinary CTGF excretion ( R = 0.83, P < 0.0001). Increased CTGF expression was also demonstrated in type 2 diabetic ob/ob mice, which points to a causal relationship between diabetes and CTGF and thus argues against a role of STZ in this process. The observed relationship of podocyte and urinary CTGF to markers of DN suggests a pathogenic role of CTGF in the development of DN.
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Ploeg, Meike C., Chantal Munts, Tayeba Seddiqi, Tim J. L. ten Brink, Jonathan Breemhaar, Lorenzo Moroni, Frits W. Prinzen, and Frans A. van Nieuwenhoven. "Culturing of Cardiac Fibroblasts in Engineered Heart Matrix Reduces Myofibroblast Differentiation but Maintains Their Response to Cyclic Stretch and Transforming Growth Factor β1." Bioengineering 9, no. 10 (October 14, 2022): 551. http://dx.doi.org/10.3390/bioengineering9100551.
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Isolation and culturing of cardiac fibroblasts (CF) induces rapid differentiation toward a myofibroblast phenotype, which is partly mediated by the high substrate stiffness of the culture plates. In the present study, a 3D model of Engineered Heart Matrix (EHM) of physiological stiffness (Youngs modulus ~15 kPa) was developed using primary adult rat CF and a natural hydrogel collagen type 1 matrix. CF were equally distributed, viable and quiescent for at least 13 days in EHM and the baseline gene expression of myofibroblast-markers alfa-smooth muscle actin (Acta2), and connective tissue growth factor (Ctgf) was significantly lower, compared to CF cultured in 2D monolayers. CF baseline gene expression of transforming growth factor-beta1 (Tgfβ1) and brain natriuretic peptide (Nppb) was higher in EHM-fibers compared to the monolayers. EHM stimulation by 10% cyclic stretch (1 Hz) increased the gene expression of Nppb (3.0-fold), Ctgf (2.1-fold) and Tgfβ1 (2.3-fold) after 24 h. Stimulation of EHM with TGFβ1 (1 ng/mL, 24 h) induced Tgfβ1 (1.6-fold) and Ctgf (1.6-fold). In conclusion, culturing CF in EHM of physiological stiffness reduced myofibroblast marker gene expression, while the CF response to stretch or TGFβ1 was maintained, indicating that our novel EHM structure provides a good physiological model to study CF function and myofibroblast differentiation.
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Wu, Shi-Bei, Tzu-Yu Hou, Hui-Chuan Kau, and Chieh-Chih Tsai. "Effect of Pirfenidone on TGF-β1-Induced Myofibroblast Differentiation and Extracellular Matrix Homeostasis of Human Orbital Fibroblasts in Graves’ Ophthalmopathy." Biomolecules 11, no. 10 (September 29, 2021): 1424. http://dx.doi.org/10.3390/biom11101424.
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Pirfenidone is a pyridinone derivative that has been shown to inhibit fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Its effect on orbital fibroblasts remains poorly understood. We investigated the in vitro effect of pirfenidone in transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation and extracellular matrix (ECM) homeostasis in primary cultured orbital fibroblasts from patients with Graves’ ophthalmopathy (GO). The expression of fibrotic proteins, including α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin, and collagen type I, was determined by Western blots. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for the ECM homeostasis were examined. After pretreating the GO orbital fibroblasts with pirfenidone (250, 500, and 750 μg/mL, respectively) for one hour followed by TGF-β1 for another 24 h, the expression of α-SMA, CTGF, fibronectin, and collagen type I decreased in a dose-dependent manner. Pretreating the GO orbital fibroblasts with pirfenidone not only abolished TGF-β1-induced TIMP-1 expression but recovered the MMP-2/-9 activities. Notably, pirfenidone inhibited TGF-β1-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), the critical mediators in the TGF-β1 pathways. These findings suggest that pirfenidone modulates TGF-β1-mediated myofibroblast differentiation and ECM homeostasis by attenuating downstream signaling of TGF-β1.
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Correll, Kelly A., Karen E. Edeen, Rachel L. Zemans, Elizabeth F. Redente, Karina A. Serban, Douglas Curran-Everett, Benjamin L. Edelman, Amanda Mikels-Vigdal, and Robert J. Mason. "Transitional human alveolar type II epithelial cells suppress extracellular matrix and growth factor gene expression in lung fibroblasts." American Journal of Physiology-Lung Cellular and Molecular Physiology 317, no. 2 (August 1, 2019): L283—L294. http://dx.doi.org/10.1152/ajplung.00337.2018.
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Epithelial-fibroblast interactions are thought to be very important in the adult lung in response to injury, but the specifics of these interactions are not well defined. We developed coculture systems to define the interactions of adult human alveolar epithelial cells with lung fibroblasts. Alveolar type II cells cultured on floating collagen gels reduced the expression of type 1 collagen (COL1A1) and α-smooth muscle actin (ACTA2) in fibroblasts. They also reduced fibroblast expression of hepatocyte growth factor (HGF), fibroblast growth factor 7 (FGF7, KGF), and FGF10. When type II cells were cultured at an air-liquid interface to maintain high levels of surfactant protein expression, this inhibitory activity was lost. When type II cells were cultured on collagen-coated tissue culture wells to reduce surfactant protein expression further and increase the expression of some type I cell markers, the epithelial cells suppressed transforming growth factor-β (TGF-β)-stimulated ACTA2 and connective tissue growth factor (CTGF) expression in lung fibroblasts. Our results suggest that transitional alveolar type II cells and likely type I cells but not fully differentiated type II cells inhibit matrix and growth factor expression in fibroblasts. These cells express markers of both type II cells and type I cells. This is probably a normal homeostatic mechanism to inhibit the fibrotic response in the resolution phase of wound healing. Defining how transitional type II cells convert activated fibroblasts into a quiescent state and inhibit the effects of TGF-β may provide another approach to limiting the development of fibrosis after alveolar injury.
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Xu, Xuefeng, Sa Luo, Biyun Li, Huaping Dai, and Jinglan Zhang. "IL-25 contributes to lung fibrosis by directly acting on alveolar epithelial cells and fibroblasts." Experimental Biology and Medicine 244, no. 9 (April 18, 2019): 770–80. http://dx.doi.org/10.1177/1535370219843827.
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Interleukin (IL)-25 is shown to potentiate type-2 immunity and contribute to chronic airway inflammation and remodeling in allergic airway diseases. However, the role of IL-25 in idiopathic pulmonary fibrosis (IPF), dominated by nonatopic type-2 immunity, still remains largely unclear. Herein, we detected the expression levels of IL-25 and IL-17BR (IL-25’s receptor) by using lung tissue samples gained from IPF patients and normal subjects. Also, by directly intranasal (IN) instillation of IL-25 to mice, we examined the potential roles and mechanisms of IL-25 in the development of lung fibrosis. Furthermore, we tested whether IL-25 can directly activate human lung fibroblast by in vitro cell culture. Immunohistochemical, Western blot, and real-time reverse transcription-polymerase chain reaction (RT-PCR) showed that the mRNA and protein levels of IL-25 and IL-17BR are significantly higher in IPF patients when compared with normal controls. Intranasal instillation of IL-25 to mice markedly induces the expressions of alveolar IL-5 and IL-13. Furthermore, immunohistochemical analysis showed that the main components of the extracellular matrix including collagen I, collagen III and fibronectin are notably induced by IL-25 instillation in lung parenchyma (especially in alveolar epithelial cells [AECs]). Also, IL-25 potentiates the expression of connective tissue growth factor (CTGF) in AECs and the recruitment of lung fibroblast. By using Cell Counting Kit-8 and EDU incorporation assay, we found that IL-25 markedly enhances the proliferation of lung fibroblast. Finally, IL-25 potentiates fibroblast to produce several fibrogenic genes including collagen I/III, fibronectin, CTGF, α smooth muscle (α-SMA) and tissue inhibitor of metalloproteinase (TIMP)-1 as determined by RT-PCR assay. Collectively, we concluded that IL-25 is increased in IPF lungs and contributes to lung fibrosis by directly mediating AECs/fibroblast activation. Impact statement Our work focused on alveolar epithelial cells (AECs)-derived type-2 cytokine (interleukin [IL]-25) in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We showed that IL-25 and IL-17BR (IL-25’s receptor) is upregulated in lung tissues (especially in AECs and lung fibroblasts) of IPF patients and contributes to lung fibrosis by directly activating lung fibroblasts and modulating epithelial–mesenchymal transition (EMT) of AECs. We suggest that IL-25 may be one of the master switches hidden in the milieu of abnormal epithelial–mesenchymal crosstalk. Treatment targeting IL-25 may be the potential and novel method for IPF patients.
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Wu, Qiuqian, and Jason H. Huang. "Ectopic expression of Smurf2 and acceleration of age-related intervertebral disc degeneration in a mouse model." Journal of Neurosurgery: Spine 27, no. 1 (July 2017): 116–26. http://dx.doi.org/10.3171/2016.11.spine16901.
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OBJECTIVELumbar intervertebral disc degeneration, an age-related process, is a major cause of low-back pain. Although low-back pain is a very common clinical problem in the aging population, no effective treatment is available, largely owing to lack of understanding of the molecular mechanisms underlying disc degeneration. The goal of this study was to characterize how ectopic expression of Smurf2 driven by the collagen Type II alpha 1 (Col2a1) promoter alters disc cell phenotype and associated cellular events, matrix synthesis, and gene expression during disc degeneration in mice.METHODSTo characterize how ectopic expression of Smurf2 in Col2a1-promoter working cells affects the disc degeneration process, the authors performed histological and immunohistochemical analysis of lumbar spine specimens harvested from wild-type (WT) and Col2a1-Smurf2 transgenic mice at various ages (n ≥ 6 in each age group). To elucidate the molecular mechanism underlying Smurf2-mediated disc degeneration, the authors isolated cells from WT and Col2a1-Smurf2 transgenic lumbar intervertebral discs and performed Western blot and real-time RT-PCR (reverse transcription polymerase chain reaction) to examine the protein and mRNA levels of interesting targets.RESULTSThe authors demonstrated that approximately 30% of WT mice at 10–12 months of age had started to show disc degeneration and that the disc degeneration process was accelerated by 3–6 months in Col2a1-Smurf2 transgenic mice. Chondrocyte-like cell proliferation, maturation, and fibrotic tissue formation in the inner annulus were often accompanied by fibroblast-to-chondrocyte differentiation in the outer annulus in transgenic discs. The chondrocyte-like cells in transgenic discs expressed higher levels of connective tissue growth factor (CTGF) than were expressed in WT counterparts.CONCLUSIONSThe findings that ectopic expression of Smurf2 driven by the Col2a1 promoter accelerated disc degeneration in Col2a1-Smurf2 transgenic mice, and that higher levels of CTGF protein and mRNA were present in Col2a1-Smurf2 transgenic discs, indicate that Smurf2 accelerates disc degeneration via upregulation of CTGF.
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McCurdy, Sarah M., Qiuxia Dai, Jianhua Zhang, Rogelio Zamilpa, Trevi A. Ramirez, Tariq Dayah, Nguyen Nguyen, Yu-Fang Jin, Amy D. Bradshaw, and Merry L. Lindsey. "SPARC mediates early extracellular matrix remodeling following myocardial infarction." American Journal of Physiology-Heart and Circulatory Physiology 301, no. 2 (August 2011): H497—H505. http://dx.doi.org/10.1152/ajpheart.01070.2010.
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Secreted protein, acidic, and rich in cysteine (SPARC) is a matricellular protein that functions in the extracellular processing of newly synthesized collagen. Collagen deposition to form a scar is a key event following a myocardial infarction (MI). Because the roles of SPARC in the early post-MI setting have not been defined, we examined age-matched wild-type (WT; n=22) and SPARC-deficient (null; n=25) mice at day 3 post-MI. Day 0 WT ( n=28) and null ( n=20) mice served as controls. Infarct size was 52 ± 2% for WT and 47 ± 2% for SPARC null ( P=NS), indicating that the MI injury was comparable in the two groups. By echocardiography, WT mice increased end-diastolic volumes from 45 ± 2 to 83 ± 5 μl ( P < 0.05). SPARC null mice also increased end-diastolic volumes but to a lesser extent than WT (39 ± 3 to 63 ± 5 μl; P < 0.05 vs. day 0 controls and vs. WT day 3 MI). Ejection fraction fell post-MI in WT mice from 57 ± 2 to 19 ± 1%. The decrease in ejection fraction was attenuated in the absence of SPARC (65 ± 2 to 28 ± 2%). Fibroblasts isolated from SPARC null left ventricle (LV) showed differences in the expression of 22 genes encoding extracellular matrix and adhesion molecule genes, including fibronectin, connective tissue growth factor (CTGF; CCN2), matrix metalloproteinase-3 (MMP-3), and tissue inhibitor of metalloproteinase-2 (TIMP-2). The change in fibroblast gene expression levels was mirrored in tissue protein extracts for fibronectin, CTGF, and MMP-3 but not TIMP-2. Combined, the results of this study indicate that SPARC deletion preserves LV function at day 3 post-MI but may be detrimental for the long-term response due to impaired fibroblast activation.
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Morinaga, Jun, Yutaka Kakizoe, Taku Miyoshi, Tomoaki Onoue, Miki Ueda, Teruhiko Mizumoto, Rika Yamazoe, et al. "The antifibrotic effect of a serine protease inhibitor in the kidney." American Journal of Physiology-Renal Physiology 305, no. 2 (July 15, 2013): F173—F181. http://dx.doi.org/10.1152/ajprenal.00586.2012.
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Interstitial fibrosis is a final common pathway for the progression of chronic kidney diseases. Activated fibroblasts have an extremely important role in the progression of renal fibrosis, and transforming growth factor (TGF)-β1 is a major activator of fibroblasts. Since previous reports have indicated that serine protease inhibitors have a potential to inhibit TGF-β1 signaling in vitro, we hypothesized that a synthetic serine protease inhibitor, camostat mesilate (CM), could slow the progression of renal fibrosis. TGF-β1 markedly increased the phosphorylation of TGF-β type I receptor, ERK 1/2, and Smad2/3 and the levels of profibrotic markers, such as α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1, in renal fibroblasts (NRK-49F cells), and they were all significantly reduced by CM. In protocol 1, 8-wk-old male Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO) and were concurrently treated with a slow-release pellet of CM or vehicle for 14 days. Protocol 2 was similar to protocol 1 except that CM was administered 7 days after UUO. CM substantially improved renal fibrosis as determined by sirius red staining, collagen expression, and hydroxyproline levels. The phosphorylation of ERK1/2 and Smad2/3 and the levels of α-SMA, CTGF, promatrix metalloproteinase-2, and matrix metalloproteinase-2 were substantially increased by UUO, and they were all significantly attenuated by CM. These antifibrotic effects of CM were also observed in protocol 2. Our present results suggest the possibility that CM might represent a new class of therapeutic drugs for the treatment of renal fibrosis through the suppression of TGF-β1 signaling.
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Allen, Joselyn Natasha, Mary Kennett, Andrew Patterson, and Pamela A. Hankey-Giblin. "Loss of MSP-dependent Ron receptor signaling exacerbates liver fibrosis in a high fat high cholesterol diet-induced ApoE KO mouse model." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 42.26. http://dx.doi.org/10.4049/jimmunol.200.supp.42.26.
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Abstract Liver fibrosis marks the turning point of non-alcoholic steatohepatitis and with no specific and effective anti-fibrotic therapies available, this disease is a major global health burden. Here, we established the novel role of the Ron receptor in mitigating liver fibrosis. For 18 weeks, apolipoprotein E (ApoE KO) and ApoE x Ron double knockout (DKO) mice were fed a fat and cholesterol-rich diet. Livers from DKO animals exhibited increased accumulation of sirius red-stained collagen. Immunohistochemistry of αSMA revealed that DKO livers had increased activation of collagen-producing hepatic stellate cells. In agreement with this, DKO livers exhibited higher expression of pro-fibrogenic molecules, PDGF, CTGF, and TGFβ. Additionally, DKO mice exhibited increased hepatic expression of collagens (Types 1, 3, and 4) and ECM remodeling proteins (MMP-2 and TIMP-1). The expression of pro-fibrogenic inflammatory cytokines (TNFα and IL-12b), receptors (TLR-4), and chemokines (MIP-2, CCL2, and CCL5) were significantly higher in DKO livers. DKO livers also exhibited increased infiltration of F4/80+ Kupffer cells, which are well-known to mediate the majority of cytokine and chemokine expression in fibrotic livers. Ron also attenuated several risk factors of liver fibrosis including insulin resistance, steatosis, hepatocellular damage, and inflammation. Despite lifestyle changes and pharmacotherapies for treating etiologies of liver fibrosis, the disrupted liver homeostasis often remains and requires effective treatments. Investigating the protective functions of Ron offers a pharmacological target for resolving the steatohepatitis spectrum.
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Yang, Ru, Jawaria Amir, Haibo Liu, and Brahim Chaqour. "Mechanical strain activates a program of genes functionally involved in paracrine signaling of angiogenesis." Physiological Genomics 36, no. 1 (December 2008): 1–14. http://dx.doi.org/10.1152/physiolgenomics.90291.2008.
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Studies were performed to examine the extent to which mechanical stimuli mediate control of angiogenesis in bladder cells both in vitro and in vivo. Differential gene expression between control nonstretched and cyclically stretched bladder smooth muscle cells was assessed using oligonucleotide microarrays and pathway analysis by the web tool Fast Assignment and Transference of Information (FatiGO). Data showed that a substantial proportion (33 of 86) of mechanically responsive genes were angiogenesis-related and include cytokines, growth-related factors, adhesion proteins, and matricellular, signal transduction, extracellular matrix (ECM), and inflammatory molecules. Integrative knowledge of protein-protein interactions revealed that 12 mechano-sensitive gene-encoded proteins have interacting partner(s) in the vascular system confirming their potential role in paracrine regulation of angiogenesis. Angiogenic genes include matricellular proteins such as Cyr61/CCN1, CTGF/CCN2 and tenascin C, components of the VEGF and IGF systems, ECM proteins such as type I collagen and proteoglycans, and matrix metalloproteinases. In an in vivo model of bladder overdistension, 5 of 11 mechano-responsive angiogenic genes, independently tested by real-time PCR, were upregulated as a result of pressure overload including Cyr61/CCN1, CTGF/CCN2, MCP-1, VEGF-A, MMP-1, and midkine. Meanwhile, the molecular anatomy of angiogenic gene promoters reveals the presence of GA box-binding for the myc-associated zinc finger protein, MAZ, often found adjacent to binding sites for mechano-responsive transcription factors (e.g., NF-κB), suggesting that the coordinated activity of these factors may induce selective angiogenic gene transcription. These data suggest that mechanical control of angiogenic genes is an integral part of the adaptive and plasticity responses to mechanical overload.
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Zhou, Xuan, Jun Xiong, Shi Lu, Lei Luo, Zhi-Lin Chen, Fan Yang, Feng Jin, et al. "Inhibitory Effect of Corilagin on miR-21-Regulated Hepatic Fibrosis Signaling Pathway." American Journal of Chinese Medicine 47, no. 07 (January 2019): 1541–69. http://dx.doi.org/10.1142/s0192415x19500794.
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Corilagin is a polyphenol that can be extracted from many medicinal plants and shows multiple pharmacological effects. We aimed to investigate the role of corilagin on miR-21-regulated hepatic fibrosis, especially miR-21-regulated TGF-[Formula: see text]1/Smad signaling pathway, in hepatic stellate LX2 cell line and Sprague–Dawley rats. The mRNA or protein levels of miR-21, Smad7, connective tissue growth factor (CTGF), [Formula: see text]-smooth muscle actin ([Formula: see text]-SMA), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-9 (MMP-9), collagen type I alpha 1 (COL1A1), Smad2, Smad3, Smad2/3, p-Smad2, p-Smad3, p-Smad2/3, and transforming growth factor-[Formula: see text]1 (TGF-[Formula: see text]1) in LX2 cells and liver tissues were determined. Furthermore, gain-of and loss-of function of miR-21 in miR-21-regulated TGF-[Formula: see text]1/Smad signaling pathway were analyzed in LX2 cells. Liver tissues and serum were collected for pathological analysis, immunohistochemical staining, and enzyme-linked immunosorbent assay (ELISA). Corilagin treatment reduced mRNA or protein levels of miR-21, CTGF, [Formula: see text]-SMA, TIMP-1, TGF-[Formula: see text]1, COL1A1, p-Smad2, p-Smad3, and p-Smad2/3 both in vitro and in vivo. While corilagin increased mRNA and protein levels of Smad7 and MMP-9. After gain-of and loss-of function of miR-21, the downstream effectors of miR-21-regulated TGF-[Formula: see text]1/Smad signaling pathway in LX2 cells changed accordingly, and the changes were inhibited by corilagin. Simultaneously, administration of corilagin not only ameliorated pathological manifestation of liver fibrosis but also reduced levels of [Formula: see text]-SMA and COL1A1 in liver tissues and TGF-[Formula: see text]1, ALT levels in serum. Corilagin is able to potentially prevent liver fibrosis by blocking the miR-21-regulated TGF-[Formula: see text]1/Smad signaling pathway in LX2 cells and CCl4-induced liver fibrosis rats, which may provide a novel therapeutic strategy for liver fibrosis.
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Huang, Xiao R., Arthur C. K. Chung, Xiao J. Wang, Kar Neng Lai, and Hui Y. Lan. "Mice overexpressing latent TGF-β1 are protected against renal fibrosis in obstructive kidney disease." American Journal of Physiology-Renal Physiology 295, no. 1 (July 2008): F118—F127. http://dx.doi.org/10.1152/ajprenal.00021.2008.
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Transforming growth factor (TGF)-β1, once activated, binds to its receptors and mediates renal fibrosis via the downstream Smad signaling pathway. We reported here that mice overexpressing latent TGF-β1 in keratinocytes were protected against renal fibrosis in a model of obstructive kidney disease. In normal mice, both transgenic (Tg) and wild-type (WT) mice had normal renal histology and function, despite a 10-fold increase in plasma latent TGF-β1 in Tg mice. A severe renal fibrosis was developed in WT mice at 7 days after urinary obstruction. Unexpectedly, renal fibrosis was prevented in Tg mice, although levels of latent TGF-β1 in both circulation and renal tissues remained high. Compared with the WT mice, quantitative real-time PCR showed that upregulation of renal α-smooth muscle actin (SMA), collagen I, and collagen III mRNA was inhibited in Tg mice (60–70% reduced, all P < 0.01). These were further confirmed by immunohistochemistry with a marked inhibition of tubulointerstitial accumulation of α-SMA+ fibroblasts, collagen I, and collagen III matrix in Tg mice (all P < 0.001). Further studies showed that inhibition of renal fibrosis in Tg mice was associated with a significant reduction in renal TGF-β1 and CTGF (60% reduced, P < 0.05), an increase in renal Smad7, a suppression of TSP-1 (a critical factor for TGF-β1 activation), and an inhibition of Smad2/3 activation (all P < 0.001). In conclusion, latent TGF-β may play a protective role in renal fibrosis. Inhibition of renal TGF-β1 expression and activation, thereby blocking the downstream TGF-β signaling pathway, may be a critical mechanism by which latent TGF-β1 protects against renal fibrosis.
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Lee, Da-Young, Sun-Mi Yun, Moon-Young Song, Sang-Deok Ji, Jong-Gon Son, and Eun-Hee Kim. "Administration of Steamed and Freeze-Dried Mature Silkworm Larval Powder Prevents Hepatic Fibrosis and Hepatocellular Carcinogenesis by Blocking TGF-β/STAT3 Signaling Cascades in Rats." Cells 9, no. 3 (February 28, 2020): 568. http://dx.doi.org/10.3390/cells9030568.
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Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide and the majority of HCC patients occur with a background of hepatic fibrosis and cirrhosis. We have previously reported the hepatoprotective effects of steamed and freeze-dried mature silkworm larval powder (SMSP) in a chronic ethanol-treated rat model. Here, we assessed the anti-fibrotic and anti-carcinogenic effects of SMSP on diethylnitrosamine (DEN)-treated rats. Wistar rats were intraperitoneally injected with DEN once a week for 12 or 16 weeks with or without SMSP administration (0.1 and 1 g/kg). SMSP administration significantly attenuated tumor foci formation and proliferation in the livers of the rats treated with DEN for 16 weeks. SMSP administration also inhibited hepatic fibrosis by decreasing the levels of collagen fiber and the expression of pro-collagen I and alpha-smooth muscle actin (α-SMA). Moreover, SMSP supplementation improved the major parameters of fibrosis such as transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1 (PAI-1), and collagen type I (Col1A1) in the livers from the rats treated with DEN for 16 weeks. As s possible mechanisms, we investigated the effects of SMSP on the TGF-β and signal transducer and activator of transcription 3 (STAT3)-mediated signaling cascades, which are known to promote hepatic fibrosis. We found that SMSP treatment inhibited the activation of TGF-β and the phosphorylation of STAT3 pathway in DEN-treated rats. Moreover, SMSP administration suppressed the expressions of the target genes of TGF-β and STAT3 induced by DEN treatment. Our findings provide experimental evidences that SMSP administration has inhibitory effects of hepatic fibrosis and HCC induced by DEN In Vivo and could be a promising strategy for the prevention or treatment of hepatic fibrosis and hepatocellular carcinogenesis.
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van Beusekom, Cyrina D., and Tanja M. Zimmering. "Profibrotic effects of angiotensin II and transforming growth factor beta on feline kidney epithelial cells." Journal of Feline Medicine and Surgery 21, no. 8 (October 22, 2018): 780–87. http://dx.doi.org/10.1177/1098612x18805862.
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Objectives The aim of this study was to evaluate the role of angiotensin II (AT-II) and its main mediator, transforming growth factor beta 1 (TGF-β1), in the development of feline renal fibrosis. Methods Expression of marker genes indicating epithelial-to-mesenchymal transition (EMT), profibrotic mediators and matricellular proteins was measured in feline kidney epithelial cells (Crandell Rees feline kidney [CRFK] cells) after incubation with AT-II and/or TGF-β1. Results Cells incubated with TGF-β1 or the combination of TGF-β1 with AT-II showed clear EMT with more stretched fibroblastic cells, whereas the cells incubated without TGF-β1 and AT-II (control) showed more epithelial cells. Gene expression of collagen type I ( COL1), tenascin-C ( TNC), trombospondin-1 ( TSP-1), connective tissue growth factor ( CTGF) and alpha-smooth muscle actin ( α-SMA) increased significantly after incubation of the CRFK cells with TGF-β1 or TGF-β1 in combination with AT-II for 12 h. As incubation of the CRFK cells with only AT-II did not show any significant rise in gene expression of the above-mentioned genes, this was further investigated. In contrast to healthy feline kidney tissue, CRFK cells showed almost no expression of the AT-II type 1 (AT1) receptor. Conclusions and relevance TGF-β1 significantly induced expression of the EMT marker gene α-SMA, profibrotic mediator CTGF, and fibrogenic proteins COL1, TNC and TSP-1 in CRFK cells. The effect of TGF-β1 on myofibroblast formation was also observed by the stretched appearance of the CRFK cells. As CRFK cells expressed almost no AT1 receptors, this cell line proved not suitable for testing the efficacy of drugs that interact with the AT1 receptor. As AT-II stimulates the effects of TGF-β1 in mammals, the results of this study suggest an indirect profibrotic effect of AT-II besides the demonstrated profibrotic effect of TGF-β1 and thus the development of feline renal fibrosis. Modulation of EMT or proliferation of myofibroblasts could serve as a diagnostic tool and a novel therapeutic target to inhibit renal fibrogenesis, and could possibly serve in the therapy of feline renal fibrosis.
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Lubel, John S., Chandana B. Herath, Jorge Tchongue, Josephine Grace, Zhiyuan Jia, Karen Spencer, David Casley, et al. "Angiotensin-(1–7), an alternative metabolite of the renin–angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat." Clinical Science 117, no. 11 (September 14, 2009): 375–86. http://dx.doi.org/10.1042/cs20080647.
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Ang-(1–7) (angiotensin-1–7), a peptide product of the recently described ACE (angiotensin-converting enzyme) homologue ACE2, opposes the harmful actions of AngII (angiotensin II) in cardiovascular tissues, but its role in liver disease is unknown. The aim of the present study was to assess plasma levels of Ang-(1–7) in human liver disease and determine its effects in experimental liver fibrosis. Angiotensin peptide levels were measured in cirrhotic and non-cirrhotic patients with hepatitis C. The effects of Ang-(1–7) on experimental fibrosis were determined using the rat BDL (bile-duct ligation) model. Liver histology, hydroxyproline quantification and expression of fibrosis-related genes were assessed. Expression of RAS (renin–angiotensin system) components and the effects of Ang-(1–7) were examined in rat HSCs (hepatic stellate cells). In human patients with cirrhosis, both plasma Ang-(1–7) and AngII concentrations were markedly elevated (P<0.001). Non-cirrhotic patients with hepatitis C had elevated Ang-(1–7) levels compared with controls (P<0.05), but AngII concentrations were not increased. In BDL rats, Ang-(1–7) improved fibrosis stage and collagen Picrosirius Red staining, and reduced hydroxyproline content, together with decreased gene expression of collagen 1A1, α-SMA (smooth muscle actin), VEGF (vascular endothelial growth factor), CTGF (connective tissue growth factor), ACE and mas [the Ang-(1–7) receptor]. Cultured HSCs expressed AT1Rs (AngII type 1 receptors) and mas receptors and, when treated with Ang-(1–7) or the mas receptor agonist AVE 0991, produced less α-SMA and hydroxyproline, an effect reversed by the mas receptor antagonist A779. In conclusion, Ang-(1–7) is up-regulated in human liver disease and has antifibrotic actions in a rat model of cirrhosis. The ACE2/Ang-(1–7)/mas receptor axis represents a potential target for antifibrotic therapy in humans.
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Schrör and Hohlfeld. "Mechanisms of anti-ischemic action of prostaglandin E1 in peripheral arterial occlusive disease." Vasa 33, no. 3 (August 1, 2004): 119–24. http://dx.doi.org/10.1024/0301-1526.33.3.119.
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The mechanisms of anti-ischemic effects of PGE1 in patients with peripheral arterial occlusive disease (PAD) are probably complex and clearly not limited to a direct vasodilator action. In addition to the known effects on blood flow, viscosity, fibrinolysis and platelet aggregation, the compound also inhibits monocyte and neutrophil function, suggesting that PGE1 will also have anti-inflammatory effects. Recent research has detected additional actions of PGE1 and prostacyclin analogs which might be relevant to its clinical efficacy. This includes inhibition of expression of adhesion molecules (E-selectin, ICAM-1, and VCAM-1), release of inflammatory cytokines (TNFalpha, MCP-1), matrix components and generation and release of growth factors (CYR61, CTGF). These actions may also contribute to the long-term effects of PGE1, particularly in more advanced stages of PAD. Gene-expression experiments with chemically stable prostacyclins and PGE1 suggest that several genes in vascular smooth muscle cells and fibroblasts are modified by prostaglandins at the transcriptional level. This includes TNFalpha-induced VCAM expression in vascular smooth muscle cells which appears to be inhibited via the prostaglandin EP2 receptor as well as IL-1-induced expression of the type-I collagen gene in fibroblasts. Thus, regulation of gene transcription by PGE1 may contribute to tissue protection in critical ischemia of the lower limbs.
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Peterson, Joshua M., Anesh Prasai, Jayson W. Jay, Steven E. Wolf, and Amina El Ayadi. "143 Galunisertib Exerts Targeted Anti-Fibrotic Effects in In Vitro Models of Burn Wound Healing." Journal of Burn Care & Research 42, Supplement_1 (April 1, 2021): S95. http://dx.doi.org/10.1093/jbcr/irab032.147.
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Abstract Introduction Inhibition of TGF-β has shown promising in vitro and in vivo results for reduction of hypertrophic scarring after burn injury. However, TGF-β regulates diverse cellular pathways apart from fibrosis, including physiologic wound healing, cell cycle control, and homeostasis. Galunisertib, a novel small molecular tyrosine kinase inhibitor of TGF-beta receptor type 1, specifically targets downstream pro-fibrotic pathways of TGF-β signaling, has an excellent adverse effect profile, and minimal off-target effects. We hypothesized that galunisertib diminishes fibrotic phenotypes in a targeted fashion, making it a promising candidate drug for prevention of hypertrophic burn scar and contracture. Methods Commercially available fibroblasts were treated with TGF-β at concentrations typical of burn wounds to induce fibrotic phenotype fibroblasts (FPF). FPF cells were treated with galunisertib for 0, 1, 2, 3, and 7 days at concentrations ranging from 0.01 μM to 100 μM. FPF viability and proliferation were assessed with MTT assay. Modulation of FPF cell fibrotic gene and was analyzed using quantitative real-time PCR (qRT-PCR) of COL1A1, COL3A1, FN1, αSMA, CTGF, DCN, MMP1, and MMP13. Analysis of phenotype modulation was performed by western blotting of P-Smad2/3, collagen-1, fibronectin, and αSMA. Statistical analysis performed with students t-test and ANOVA. Results TGF-β treated FPF cells had significantly increased proliferation relative to commercially available fibroblasts, which was attenuated by treatment with 2.5–10 μM galunisertib at 2 or 3 days after treatment in a concentration dependent manner (p < 0.05) while also not causing a relative decrease in proliferation. Expression of FPF downstream pro-fibrotic genes underwent significant fold changes (FN1, αSMA, CTGF: p < 0.05). Protein expression showed decrease in both SMAD2/3 phosphorylation and fibrotic protein expression. Scratch assay analysis is ongoing. Conclusions Galunisertib exerts targeted dose-dependent inhibition of fibrotic gene expression and phenotypes in vitro without hindering cellular proliferation.
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Qiu, Ming, Huanyu Shu, Lu Li, Yejiao Shen, Yunfan Tian, Yue Ji, Wei Sun, Yan Lu, and Xiangqing Kong. "Interleukin 10 Attenuates Angiotensin II-Induced Aortic Remodelling by Inhibiting Oxidative Stress-Induced Activation of the Vascular p38 and NF-κB Pathways." Oxidative Medicine and Cellular Longevity 2022 (April 26, 2022): 1–15. http://dx.doi.org/10.1155/2022/8244497.
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Interleukin 10 (IL-10) is a probable anti-inflammatory factor that can attenuate hypertrophic remodelling caused by overloaded pressure and improve cardiac function. In this study, IL-10 was decreased in both the plasma of hypertensive patients and the aortic vessels of angiotensin II (Ang II)-induced hypertensive mice. IL-10 was unable to alter blood pressure in the case of Ang II-induced hypertension. The aortic thickness, collagen deposition, and the levels of fibrosis-associated markers, including collagen type I α 1 (Col1α1), connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and matrix metalloproteinase 2 (MMP2), were significantly reduced in the IL-10 treatment group compared with the vehicle group after Ang II treatment. Moreover, IL-10 treatment significantly inhibited the number of CD45+ positive cells and the mRNA expression levels of proinflammatory cytokines in the vascular tissue of Ang II-infused mice. Furthermore, dihydroethidium (DHE) and 4hydroxynonenal (4-HNE) staining showed that IL-10 decreased Ang II-induced vascular oxidative stress and lipid peroxidation. Furthermore, IL-10 suppressed Ang II-induced proliferation, fibrosis, and inflammation of mouse vascular adventitial fibroblasts (mVAFs). Mechanistically, IL-10 suppressed the phosphorylation of p38 mitogen-activated protein (MAP) kinase and nuclear factor-κB (NF-κB) in Ang II-induced vascular fibrosis. In summary, our data indicated that IL-10, as a potential therapeutic target treatment, could limit the progression of Ang II-induced aortic remodelling.
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Qiu, Ming, Huanyu Shu, Lu Li, Yejiao Shen, Yunfan Tian, Yue Ji, Wei Sun, Yan Lu, and Xiangqing Kong. "Interleukin 10 Attenuates Angiotensin II-Induced Aortic Remodelling by Inhibiting Oxidative Stress-Induced Activation of the Vascular p38 and NF-κB Pathways." Oxidative Medicine and Cellular Longevity 2022 (April 26, 2022): 1–15. http://dx.doi.org/10.1155/2022/8244497.
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Interleukin 10 (IL-10) is a probable anti-inflammatory factor that can attenuate hypertrophic remodelling caused by overloaded pressure and improve cardiac function. In this study, IL-10 was decreased in both the plasma of hypertensive patients and the aortic vessels of angiotensin II (Ang II)-induced hypertensive mice. IL-10 was unable to alter blood pressure in the case of Ang II-induced hypertension. The aortic thickness, collagen deposition, and the levels of fibrosis-associated markers, including collagen type I α 1 (Col1α1), connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and matrix metalloproteinase 2 (MMP2), were significantly reduced in the IL-10 treatment group compared with the vehicle group after Ang II treatment. Moreover, IL-10 treatment significantly inhibited the number of CD45+ positive cells and the mRNA expression levels of proinflammatory cytokines in the vascular tissue of Ang II-infused mice. Furthermore, dihydroethidium (DHE) and 4hydroxynonenal (4-HNE) staining showed that IL-10 decreased Ang II-induced vascular oxidative stress and lipid peroxidation. Furthermore, IL-10 suppressed Ang II-induced proliferation, fibrosis, and inflammation of mouse vascular adventitial fibroblasts (mVAFs). Mechanistically, IL-10 suppressed the phosphorylation of p38 mitogen-activated protein (MAP) kinase and nuclear factor-κB (NF-κB) in Ang II-induced vascular fibrosis. In summary, our data indicated that IL-10, as a potential therapeutic target treatment, could limit the progression of Ang II-induced aortic remodelling.
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Lu, H. K., H. P. Chou, C. L. Li, M. Y. Wang, and L. F. Wang. "Stimulation of Cells Derived from Nifedipine-induced Gingival Overgrowth with Porphyromonas gingivalis, Lipopolysaccharide, and Interleukin-1β." Journal of Dental Research 86, no. 11 (November 2007): 1100–1104. http://dx.doi.org/10.1177/154405910708601115.
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The purpose of this study was to clarify the main contributory factor of nifedipine-induced gingival overgrowth either by Porphyromonas gingivalis lipopolysaccharide ( Pg-LPS) or interleukin-1beta (IL-1β). Human gingival fibroblasts from healthy tissues and nifedipine-induced gingival overgrowth tissues were stimulated with nifedipine, IL-1β, Escherichia coli lipopolysaccharide ( Ec-LPS), and Pg-LPS, and the gene expressions were analyzed by RT-PCR. Analysis of the data showed no strong evidence of a synergistic effect of nifedipine and Pg-LPS on IL-6, connective tissue growth factor (CTGF), and type 1 collagen gene expression of either healthy cells or nifedipine-induced gingival overgrowth cells. Among the three stimulants—IL-1β, Pg-LPS, and Ec-LPS—androgen receptor and IL-6 gene expressions in both the healthy and nifedipine-induced gingival overgrowth groups were strongly up-regulated by the presence of IL-1β only. Furthermore, the responses to IL-1β in the nifedipine-induced gingival overgrowth group were stronger than those of the healthy group. It can be concluded that IL-1β is an important mediator responsible for the higher IL-6 and androgen receptor expression of nifedipine-induced gingival overgrowth cells.
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Trink, Jackie, Renzhong Li, Yaseelan Palarasah, Stéphan Troyanov, Thomas E. Andersen, Johannes J. Sidelmann, Mark D. Inman, Salvatore V. Pizzo, Bo Gao, and Joan C. Krepinsky. "Activated Alpha 2-Macroglobulin Is a Novel Mediator of Mesangial Cell Profibrotic Signaling in Diabetic Kidney Disease." Biomedicines 9, no. 9 (August 30, 2021): 1112. http://dx.doi.org/10.3390/biomedicines9091112.
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Diabetic kidney disease (DKD) is caused by the overproduction of extracellular matrix proteins (ECM) by glomerular mesangial cells (MCs). We previously showed that high glucose (HG) induces cell surface translocation of GRP78 (csGRP78), mediating PI3K/Akt activation and downstream ECM production. Activated alpha 2-macroglobulin (α2M*) is a ligand known to initiate this signaling cascade. Importantly, increased α2M was observed in diabetic patients’ serum, saliva, and glomeruli. Primary MCs were used to assess HG responses. The role of α2M* was assessed using siRNA, a neutralizing antibody and inhibitory peptide. Kidneys from type 1 diabetic Akita and CD1 mice and human DKD patients were stained for α2M/α2M*. α2M transcript and protein were significantly increased with HG in vitro and in vivo in diabetic kidneys. A similar increase in α2M* was seen in media and kidneys, where it localized to the mesangium. No appreciable α2M* was seen in normal kidneys. Knockdown or neutralization of α2M/α2M* inhibited HG-induced profibrotic signaling (Akt activation) and matrix/cytokine upregulation (collagen IV, fibronectin, CTGF, and TGFβ1). In patients with established DKD, urinary α2M* and TGFβ1 levels were correlated. These data reveal an important role for α2M* in the pathogenesis of DKD and support further investigation as a potential novel therapeutic target.
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Castillero, Estibaliz, Hirokazu Akashi, Marc Najjar, Ruiping Ji, Lea Maria Brandstetter, Catherine Wang, Xianghai Liao, et al. "Activin type II receptor ligand signaling inhibition after experimental ischemic heart failure attenuates cardiac remodeling and prevents fibrosis." American Journal of Physiology-Heart and Circulatory Physiology 318, no. 2 (February 1, 2020): H378—H390. http://dx.doi.org/10.1152/ajpheart.00302.2019.
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Myostatin (MSTN) is a transforming growth factor (TGF)-β superfamily member that acts as a negative regulator of muscle growth and may play a role in cardiac remodeling. We hypothesized that inhibition of activin type II receptors (ACTRII) to reduce MSTN signaling would reduce pathological cardiac remodeling in experimental heart failure (HF). C57BL/6J mice underwent left anterior descending coronary artery ligation under anesthesia to induce myocardial infarction (MI) or no ligation (sham). MI and sham animals were each randomly divided into groups ( n ≥ 10 mice/group) receiving an ACTRII or ACTRII/TGFβ receptor-signaling inhibiting strategy: 1) myo-Fc group (weekly 10 mg/kg Myo-Fc) or 2) Fol + TGFi group (daily 12 µg/kg follistatin plus 2 mg/kg TGFβ receptor inhibitor), versus controls. ACTRII/TGFBR signaling inhibition preserved cardiac function by echocardiography and prevented an increase in brain natriuretic peptide (BNP). ACTRII/TGFBR inhibition resulted in increased phosphorylation (P) of Akt and decreased P-p38 mitogen-activated protein kinase (MAPK) in MI mice. In vitro, Akt contributed to P-SMAD2,3, P-p38, and BNP regulation in cardiomyocytes. ACTRII/TGFBR inhibition increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) levels and decreased unfolded protein response (UPR) markers in MI mice. ACTRII/TGFBR inhibition was associated with a decrease in cardiac fibrosis and fibrosis markers, connective tissue growth factor (CTGF), type I collagen, fibronectin, α-smooth muscle actin, and matrix metalloproteinase (MMP)-12 in MI mice. MSTN exerted a direct regulation on the UPR marker eukaryotic translation initiation factor-2α (eIf2α) in cardiomyocytes. Our study suggests that ACTRII ligand inhibition has beneficial effects on cardiac signaling and fibrosis after ischemic HF. NEW & NOTEWORTHY Activin type II receptor ligand inhibition resulted in preserved cardiac function, a decrease in cardiac fibrosis, improved SERCA2a levels, and a prevention of the unfolded protein response in mice with myocardial infarction.
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Subramanian, Umadevi, Chandramohan Ramasamy, Samivel Ramachandran, Joshua M. Oakes, Jason D. Gardner, and Kailash N. Pandey. "Genetic Disruption of Guanylyl Cyclase/Natriuretic Peptide Receptor-A Triggers Differential Cardiac Fibrosis and Disorders in Male and Female Mutant Mice: Role of TGF-β1/SMAD Signaling Pathway." International Journal of Molecular Sciences 23, no. 19 (September 29, 2022): 11487. http://dx.doi.org/10.3390/ijms231911487.
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The global targeted disruption of the natriuretic peptide receptor-A (NPRA) gene (Npr1) in mice provokes hypertension and cardiovascular dysfunction. The objective of this study was to determine the mechanisms regulating the development of cardiac fibrosis and dysfunction in Npr1 mutant mice. Npr1 knockout (Npr1−/−, 0-copy), heterozygous (Npr1+/−, 1-copy), and wild-type (Npr1+/+, 2-copy) mice were treated with the transforming growth factor (TGF)-β1 receptor (TGF-β1R) antagonist GW788388 (2 µg/g body weight/day; ip) for 28 days. Hearts were isolated and used for real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical analyses. The Npr1−/− (0-copy) mice showed a 6-fold induction of cardiac fibrosis and dysfunction with markedly induced expressions of collagen-1α (3.8-fold), monocyte chemoattractant protein (3.7-fold), connective tissue growth factor (CTGF, 5.3-fold), α-smooth muscle actin (α-SMA, 6.1-fold), TGF-βRI (4.3-fold), TGF-βRII (4.7-fold), and phosphorylated small mothers against decapentaplegic (pSMAD) proteins, including pSMAD-2 (3.2-fold) and pSMAD-3 (3.7-fold), compared with wild-type mice. The expressions of phosphorylated extracellular-regulated kinase ERK1/2 (pERK1/2), matrix metalloproteinases-2, -9, (MMP-2, -9), and proliferating cell nuclear antigen (PCNA) were also significantly upregulated in Npr1 0-copy mice. The treatment of mutant mice with GW788388 significantly blocked the expression of fibrotic markers, SMAD proteins, MMPs, and PCNA compared with the vehicle-treated control mice. The treatment with GW788388 significantly prevented cardiac dysfunctions in a sex-dependent manner in Npr1 0-copy and 1-copy mutant mice. The results suggest that the development of cardiac fibrosis and dysfunction in mutant mice is predominantly regulated through the TGF-β1-mediated SMAD-dependent pathway.
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Yoon, Jung Joo, Yun Jung Lee, Dae Gill Kang, and Ho Sub Lee. "Protective Role of Oryeongsan Against Renal Inflammation and Glomerulosclerosis in db/db Mice." American Journal of Chinese Medicine 42, no. 06 (January 2014): 1431–52. http://dx.doi.org/10.1142/s0192415x14500906.
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Diabetic nephropathy is characterized by renal hardening and interstitial fibrosis caused by extracellular matrix (ECM) accumulation. The most distinctive diabetic lesion in the glomeruli is mesangial expansion and hyperplasia, which ultimately leads to diabetic nephrosclerosis. Oryeongsan (ORS), a traditional Chinese herbal medication, is widely used to treat nephrosis, dropsy, and uremia. In this study, type 2 diabetic animals (db/db mice) were administered ORS (100 mg/kg/day) for 8 weeks to examine the potential beneficial effects on metabolic abnormalities and diabetic nephropathy progression, including renal fibrosis. The body weight, total-cholesterol, triglyceride, and LDL-c levels were significantly decreased in ORS-treated db/db mice compared to untreated db/db mice. In addition, the blood glucose, insulin, glucose tolerance, and the homeostasis model assessment of insulin resistance index (HOMA-IR) were significantly improved in ORS-treated db/db mice compared to untreated db/db mice. Creatinine clearance (Ccr), urine albumin, and BUN levels were also improved by ORS treatment. The ratio of mesangial matrix/glomerular area was markedly higher in db/db mice than in db/m mice, but ORS significantly reduced this expansion. TGF-β1, Smad-2/-4, Collagen IV, CTGF, and TIMP decreased with ORS treatment, as were Smad-7 and MT1-MMP in ORS-treated db/db mice. Furthermore, ICAM-1 and MCP-1 expression were suppressed in ORS-treated db/db mice. Therefore, these findings suggest that ORS ameliorated insulin resistance and diabetes-associated glomerulosclerosis in db/db mice, possibly by disturbing the TGF-β1/Smads pathway. ORS may be a new therapeutic option for treating diabetic nephropathy.
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Kennedy, David, Fatimah Khalaf, Brendan Sheehy, Malory Weber, Brendan Agatisa-Boyle, Julijana Conic, Kayla Hauser, et al. "Telocinobufagin, a Novel Cardiotonic Steroid, Promotes Renal Fibrosis via Na+/K+-ATPase Profibrotic Signaling Pathways." International Journal of Molecular Sciences 19, no. 9 (August 29, 2018): 2566. http://dx.doi.org/10.3390/ijms19092566.
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Cardiotonic steroids (CTS) are Na+/K+-ATPase (NKA) ligands that are elevated in volume-expanded states and associated with cardiac and renal dysfunction in both clinical and experimental settings. We test the hypothesis that the CTS telocinobufagin (TCB) promotes renal dysfunction in a process involving signaling through the NKA α-1 in the following studies. First, we infuse TCB (4 weeks at 0.1 µg/g/day) or a vehicle into mice expressing wild-type (WT) NKA α-1, as well as mice with a genetic reduction (~40%) of NKA α-1 (NKA α-1+/−). Continuous TCB infusion results in increased proteinuria and cystatin C in WT mice which are significantly attenuated in NKA α-1+/− mice (all p < 0.05), despite similar increases in blood pressure. In a series of in vitro experiments, 24-h treatment of HK2 renal proximal tubular cells with TCB results in significant dose-dependent increases in both Collagens 1 and 3 mRNA (2-fold increases at 10 nM, 5-fold increases at 100 nM, p < 0.05). Similar effects are seen in primary human renal mesangial cells. TCB treatment (100 nM) of SYF fibroblasts reconstituted with cSrc results in a 1.5-fold increase in Collagens 1 and 3 mRNA (p < 0.05), as well as increases in both Transforming Growth factor beta (TGFb, 1.5 fold, p < 0.05) and Connective Tissue Growth Factor (CTGF, 2 fold, p < 0.05), while these effects are absent in SYF cells without Src kinase. In a patient study of subjects with chronic kidney disease, TCB is elevated compared to healthy volunteers. These studies suggest that the pro-fibrotic effects of TCB in the kidney are mediated though the NKA-Src kinase signaling pathway and may have relevance to volume-overloaded conditions, such as chronic kidney disease where TCB is elevated.
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Sánchez-López, Elsa, Juan Rodriguez-Vita, Cecile Cartier, Monica Rupérez, Vanesa Esteban, Gisselle Carvajal, Raquel Rodrígues-Díez, Juan José Plaza, Jesús Egido, and Marta Ruiz-Ortega. "Inhibitory effect of interleukin-1β on angiotensin II-induced connective tissue growth factor and type IV collagen production in cultured mesangial cells." American Journal of Physiology-Renal Physiology 294, no. 1 (January 2008): F149—F160. http://dx.doi.org/10.1152/ajprenal.00129.2007.
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Connective tissue growth factor (CTGF) is overexpressed in kidney diseases associated with extracellular matrix accumulation. Angiotensin II (ANG II) participates in renal fibrosis by the upregulation of growth factors, including CTGF, and extracellular matrix proteins, such as type IV collagen. During renal injury, ANG II and the macrophage-produced cytokine interleukin-1β (IL-1β) may be present simultaneously in the glomerular environment. However, there are no studies about the interaction between ANG II and IL-1β in renal fibrosis. For this reason, in cultured mesangial cells (MC), we investigated whether IL-1β could regulate ANG II-mediated collagen accumulation and the mechanisms underlying this process. In MC, CTGF is a downstream mediator of type IV collagen production induced by ANG II. IL-1β did not increase the production of CTGF and type IV collagen but significantly inhibited ANG II-induced CTGF and type IV collagen overexpression. Moreover, IL-1β also inhibited type IV collagen upregulation caused by exogenous recombinant CTGF. Matrix metalloproteinase-9 (MMP-9) is the main enzyme involved in type IV collagen degradation. In MC, coincubation of IL-1β and ANG II caused a synergistic increase in MMP-9 gene expression and activity, associated with type IV collagen inhibition. The described IL-1β effects were dependent on activation of ERK/MAPK but independent p38-MAPK, JNK, phosphatidylinositol 3-kinase/Akt, and Rho-associated kinase pathways. In summary, these data indicate that IL-1β inhibited ANG II-mediated type IV collagen production, via CTGF downregulation, and increased type IV collagen degradation, through MMP-9 upregulation. Our in vitro data show that the proinflammatory cytokine IL-1β abrogates ANG II-induced CTGF production, describing antagonistic activities of proinflammatory cytokines on ANG II actions.
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Ding, Luo-Bin, Yao Li, Guang-Yuan Liu, Tai-Hang Li, Feng Li, Jian Guan, and Hua-Jun Wang. "Long non-coding RNA PVT1, a molecular sponge of miR-26b, is involved in the progression of hyperglycemia-induced collagen degradation in human chondrocytes by targeting CTGF/TGF-β signal ways." Innate Immunity 26, no. 3 (October 18, 2019): 204–14. http://dx.doi.org/10.1177/1753425919881778.
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The current study was conducted to investigate the role of long non-coding RNA PVT1 in hyperglycemia-triggered human osteoarthritis (OA) chondrocytes. Cartilage from knee OA patients with and without diabetes, as well as normal cartilage, was obtained. Isolated human chondrocytes were treated with 30 nM of Glc with or without pioglitazone. The expression levels of PVT1, miR-26b, and type II collagen were determined by RT-PCR. Type II collagen was detected by immunocytochemistry and chondrocytes were stained with Alcian blue. Moreover, the interaction among PVT1, miR-26b, and CTGF was examined using bioinformatics, FISH, RIP, RNA-pull down, and luciferase reporter assays. Over-expression of PVT1 and miR-26b were performed and expressions of CTGF, TGF-β1, SMAD3, MMP-13, and type II collagen proteins were examined. Significantly higher expression of PVT1 was observed in diabetic OA. High Glc induced the elevated expression of PVT1, CTGF, TGF-β1, IL-6, and MMP-13, as well as decreased expression of type II collagen and miR-26b. These alterations could be reversed by pioglitazone. PVT1 acted as a sponge for miR-26b to facilitate CTGF expression. Over-expression of PVT1 increased the expressions of CTGF, TGF-β1, SMAD3, and MMP-13 and decreased expression of type II collagen. Our findings confirmed that PVT1 is involved in the hyperglycemia-induced collagen degradation, via the miR-26b-CTGF-TGF-β1-axis.
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Yoon, Jung Joo, Hyeon Kyoung Lee, Hye Yoom Kim, Byung Hyuk Han, Ho Sub Lee, Yun Jung Lee, and Dae Gill Kang. "Sauchinone Protects Renal Mesangial Cell Dysfunction against Angiotensin II by Improving Renal Fibrosis and Inflammation." International Journal of Molecular Sciences 21, no. 19 (September 23, 2020): 7003. http://dx.doi.org/10.3390/ijms21197003.
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Abnormal and excessive growth of mesangial cells is important in the pathophysiologic processes of diabetes-associated interstitial fibrosis and glomerulosclerosis, leading to diabetic nephropathy, which eventually turns into end-stage renal disease. Sauchinone, a biologically-active lignan isolated from aerial parts of Saururus chinensis, has anti-inflammatory and anti-viral activities effects on various cell types. However, there are no studies reporting the effects of sauchinone on diabetic nephropathy. The present study aims to investigate the role of sauchinone in mesangial cell proliferation and fibrosis induced by angiotensin II, as well as the underlying mechanisms of these processes. Human renal mesangial cells were induced by angiotensin II (AngII, 10 μM) in the presence or absence of sauchinone (0.1–1 μM) and incubated for 48 h. In this study, we found that AngII induced mesangial cell proliferation, while treatment with sauchinone inhibited the cell proliferation in a dose-dependent manner. Pre-treatment with sauchinone induced down-regulation of cyclins/CDKs and up-regulation of CDK inhibitor, p21, and p27kip1 expression. In addition, AngII-enhanced expression of fibrosis biomarkers such as fibronectin, collagen IV, and connective tissue growth factor (CTGF), which was markedly attenuated by sauchinone. Sauchinone also decreased AngII-induced TGF-β1 and Smad-2, Smad-3, and Smad-4 expression. This study further revealed that sauchinone ameliorated AngII-induced mesangial inflammation through disturbing activation of inflammatory factors, and NLRP3 inflammasome, which is composed of the NLRP3 protein, procaspase-1, and apoptosis-associated speck-like protein containing a CARD (ASC). Moreover, pretreatment of sauchinone inhibited NF-κB translocation and ROS production in AngII-exposed mesangial cells. These data suggest that sauchinone has a protective effect on renal proliferation, fibrosis and inflammation. Therefore, sauchinone might be a potential pharmacological agent in prevention of AngII-induced renal damage leading to diabetic nephropathy.
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Sharifi-Sanjani, Maryam, Mariah Berman, Dmitry Goncharov, Mohammad Alhamaydeh, Theodore Guy Avolio, Jeffrey Baust, Baojun Chang, et al. "Yes-Associated Protein (Yap) Is Up-Regulated in Heart Failure and Promotes Cardiac Fibroblast Proliferation." International Journal of Molecular Sciences 22, no. 11 (June 7, 2021): 6164. http://dx.doi.org/10.3390/ijms22116164.
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Left ventricular (LV) heart failure (HF) is a significant and increasing cause of death worldwide. HF is characterized by myocardial remodeling and excessive fibrosis. Transcriptional co-activator Yes-associated protein (Yap), the downstream effector of HIPPO signaling pathway, is an essential factor in cardiomyocyte survival; however, its status in human LV HF is not entirely elucidated. Here, we report that Yap is elevated in LV tissue of patients with HF, and is associated with down-regulation of its upstream inhibitor HIPPO component large tumor suppressor 1 (LATS1) activation as well as upregulation of the fibrosis marker connective tissue growth factor (CTGF). Applying the established profibrotic combined stress of TGFβ and hypoxia to human ventricular cardiac fibroblasts in vitro increased Yap protein levels, down-regulated LATS1 activation, increased cell proliferation and collagen I production, and decreased ribosomal protein S6 and S6 kinase phosphorylation, a hallmark of mTOR activation, without any significant effect on mTOR and raptor protein expression or phosphorylation of mTOR or 4E-binding protein 1 (4EBP1), a downstream effector of mTOR pathway. As previously reported in various cell types, TGFβ/hypoxia also enhanced cardiac fibroblast Akt and ERK1/2 phosphorylation, which was similar to our observation in LV tissues from HF patients. Further, depletion of Yap reduced TGFβ/hypoxia-induced cardiac fibroblast proliferation and Akt phosphorylation at Ser 473 and Thr308, without any significant effect on TGFβ/hypoxia-induced ERK1/2 activation or reduction in S6 and S6 kinase activities. Taken together, these data demonstrate that Yap is a mediator that promotes human cardiac fibroblast proliferation and suggest its possible contribution to remodeling of the LV, opening the door to further studies to decipher the cell-specific roles of Yap signaling in human HF.
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Chiu, Y. H., J. Spierings, J. M. Van Laar, J. De Vries-Bouwstra, M. Van Dijk, and R. Goldschmeding. "POS0469 ENDOTHELIAL TO MESENCHYMAL TRANSITION AND SENESCENCE ARE PART OF THE FIBROTIC PATHOGENESIS IN SYSTEMIC SCLEROSIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 488.3–489. http://dx.doi.org/10.1136/annrheumdis-2022-eular.76.
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BackgroundSystemic sclerosis (SSc) is a systemic autoimmune disease characterised by inflammation, vasculopathy and fibrosis. Several mechanisms, including endothelial to mesenchymal transition (EndMT) and cellular senescence, may be included in the fibrosis process, especially in response to inflammation and vasculopathy.ObjectivesOur study aimed to identify how EndMT and cellular senescence manifest in SSc skin fibrosis.MethodsWe performed a cross-sectional biobank study on formalin-fixed, paraffin-embedded skin biopsies from patients meeting the ACR/EULAR 2013 classification criteria for SSc. The extent of dermal fibrosis and inflammatory cell infiltration was scored on haematoxylin-eosin stained samples. Fibrosis severity was semi-quantified by the compactness of collagen bundles and scored from one to three. The presence of senescence was defined by P21 or P16 positivity without co-localised Ki-67. The expression of P16, P21, and CTGF on fibroblasts and endothelia was scored from zero to two. The semi-quantitative score was evaluated independently in the superficial and deep dermis by agreement of two researchers (MRD and YHC). EndMT was assessed by co-localisation of CD31 and α-SMA double staining by immunofluorescence, and enclosure of ERG positive endothelial cell nuclei by α-SMA stained cytoplasm under bright field. Lymph vessels were identified by D2-40 (podoplanin) staining, and density was assessed.ResultsIn total, skin biopsies from 18 SSc patients and four age-matched healthy controls were investigated. The characteristics of the patients are listed in Table 1. The dermal fibrosis score revealed a correlation with modified Rodnan skin score (Figure 1A).Table 1.Clinical features of 18 patients with systemic sclerosisAge, median (IQR)47 (21)Female, n (%)11 (61)Biopsy site, n (%) Upper limb3 (17) Trunk6 (33) Lower limb8 (44)Type of SSc, n (%) Limited cutaneous SSc13 (72) Diffuse cutaneous SSc5 (28)mRSS, median (IQR)4 (9)Anti-topoisomerase I antibody positive, n (%)3 (17)Anti-RNA polymerase 3 positive, n (%)2 (11)Anti-centromere positive, n (%)3 (17)SSc, systemic sclerosis; IQR, interquartile range; mRSS, modified Rodnan skin score.Figure 1.(A) The modified Rodnan skin score (mRSS) was higher in skin biopsies with severe fibrosis. (B) While merging superficial and deep dermis semi-quantitative scores, increased senescence marker was associated with increased CTGF expression on fibroblasts. (C) Endothelial to mesenchymal transition (EndMT) was more in systemic sclerosis skin without difference between groups with various fibrosis severity. (D)EndMT was associated with increased senescence markers on fibroblasts.Senescence markers showed higher expression on fibroblasts from highly fibrotic dermis than healthy control. The median (IQR) percentage of P16 positive fibroblasts in dermis was 0.7 (0.5) in healthy controls, 0.9 (0.7) in grade one fibrosis, 0.5 (0.5) in grade two fibrosis, and 6.0 (4.6) in grade three fibrosis (p = 0.144). The median (IQR) percentage of P21 positive fibroblasts in dermis was 3.3 (7.0) in healthy controls, 10.3 (11.8) in grade one fibrosis, 33.2 (19.2) in grade two fibrosis, and 32.9 (40.7) in grade three fibrosis (p = 0.042). Moreover, increase of senescence markers on fibroblasts was associated with increased CTGF expression (Figure 1B).The density of blood and lymphatic vessels did not correlate with fibrosis severity. Still, the frequency of EndMT was significantly higher in patients with SSc, although it did not differ between groups with various fibrosis severity (Figure 1C). EndMT was not observed in lymphatic vessels (i.e. there was no co-localisation of D2-40 and α-SMA). Finally, the frequency of EndMT was increased with stronger fibroblast senescence (Figure 1D).ConclusionEndMT and fibroblast senescence were more prominent in SSc skin compared to healthy control skin. Strong fibroblast senescence was associated with EndMT. Fibroblast senescence might facilitate EndMT and be involved in SSc fibrosis.Disclosure of InterestsYu-Hsiang Chiu: None declared, Julia Spierings Grant/research support from: J. Spierings has received a grant from Boehringer., Jacob M. van Laar Consultant of: J. M. van Laar has received honoraria from Abbvie, Arxx Tx, Galapagos, Gesyntha, Leadiant, and Roche., Grant/research support from: J.M. van Laar has received grants from Boehringer, Astra Zeneca, MSD, and Roche., Jeska de Vries-Bouwstra: None declared, Marijke van Dijk: None declared, Roel Goldschmeding: None declared.
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Ouyang, Xiaosen, Thu H. Le, Carlos Roncal, Christine Gersch, Jaime Herrera-Acosta, Bernardo Rodriguez-Iturbe, Thomas M. Coffman, Richard J. Johnson, and Wei Mu. "Th1 inflammatory response with altered expression of profibrotic and vasoactive mediators in AT1A and AT1B double-knockout mice." American Journal of Physiology-Renal Physiology 289, no. 4 (October 2005): F902—F910. http://dx.doi.org/10.1152/ajprenal.00141.2005.
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AT1 double receptor (AT1A and AT1B) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT1 double-knockout mice. We examined the renal expression of various mediator systems in control ( n = 6) vs. double-knockout mice ( n = 6) at 3–5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT1 double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-α, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4+ and CD11b+ cells, increased fibrosis-associated mediators (CTGF, TGF-β and TNF-α mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with controls ( P < 0.05 for all markers). These changes were associated with increased mRNA expression of endothelin (ET)-1 and ET-A receptor ( P < 0.05), cyclooxygenase (COX)-2/TXA2 synthase ( P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS ( P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT1 double-knockout mice by Western blot analysis ( P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT2 receptor mRNA expression was not significantly different from wild-type mice. In conclusion, the absence of the AT1 receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype.
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Meng, YH, C. Tian, L. Liu, L. Wang, and Q. Chang. "Elevated expression of connective tissue growth factor, osteopontin and increased collagen content in human ascending thoracic aortic aneurysms." Vascular 22, no. 1 (May 13, 2013): 20–27. http://dx.doi.org/10.1177/1708538112472282.
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Little is known about the molecular mechanisms of ascending thoracic aortic aneurysms (ATAAs). Abnormal extracellular matrix changes and variations of vascular smooth muscle cells (VSMCs) have been implicated in abdominal aortic aneurysm formation. Our objective was to investigate the alterations of collagen, stimulators of collagen synthesis and synthetic VSMCs in patients with ATAA. Surgical samples from ATAA were taken from 20 patients, and 18 control aortas were obtained during coronary artery bypass surgery. All aortic wall specimens were fixed for histology and immunohistochemistry for collagen, connective tissue growth factor (CTGF) and osteopontin. Realtime polymerase chain reaction was used to determine their mRNA expression. Histology and semi-quantitative analysis demonstrated that protein levels of collagen, CTGF and osteopontin significantly increased by 1.9-, 1.4- and 2.2-fold, respectively ( P < 0.01 for all) in the ATAA group than in the control group. Similar results were shown in mRNA levels of type Iα1and IIIα1 collagen, CTGF and osteopontin. The protein levels of CTGF and osteopontin were positively correlated with aortic diameter ( r = 0.67, r = 0.73; P < 0.01 for both). In conclusion, overexpression of aortic CTGF and synthetic VSMCs marker (osteopontin), which is likely to be responsible for elevated aortic collagen content, may provide a potential mechanism for aneurysmal enlargement.
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Del Papa, N., M. Lorini, V. Carbonelli, A. Minniti, F. Pignataro, W. Maglione, G. Di Luca, N. Montano, and R. Caporali. "AB0153 ADIPOSE-DERIVED STROMAL/STEM CELLS FROM SYSTEMIC SCLEROSIS PATIENTS SUCCESSFULLY EXERT A PARACRINE ANTI-FIBROTIC ACTIVITY AND INDUCE A PRO-ANGIOGENIC PHENOTYPE OF SCLERODERMA FIBROBLASTS IN VITRO." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1377.2–1377. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3248.
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Background:Adipose-derived stromal/stem cells (ADSCs) are multipotential non-hematopoietic progenitor cells with anti-inflammatory, immunomodulatory and regenerative effects. They have the advantage of accessibility and potent pro-angiogenic effects when compared with other stem cells, such as bone-marrow derived stem cells. Recent studies have shown that autologous fat grafting may be effective in the treatment of fibrotic and vascular complications in systemic sclerosis (SSc), despite a pro-fibrotic signature.Objectives:Aim of the study was to better characterize the proliferative and secretive profile of ADSCs in normoxic and hypoxic conditions, and to evaluate the mechanisms by which ADSCs exert these observed clinical effects.Methods:Adipose tissue samples were obtained by liposuction from 12 SSc patients and 10 healthy donors (HD). ADSCs were purified according to their adherence to the plastic and characterized to express specific MSC surface antigens by flow cytometry analysis. Proliferation of ADSCs from SSc patients and normal controls was evaluated in normoxic and hypoxic conditions. Fibroblasts and ADSCs derived from SSc patients were co-cultured in direct and indirect culture systems and compared to HD. Fibroblasts proliferation, mRNA expression and protein secretion of VEGF and known fibrotic mediators including TGF β-1, TGFR, CTGF, Collagen type I (Col I) were analyzed in the same conditions.Results:Normoxic and hypoxic culture conditions did not modify the proliferation rate of both normal and SSc ADSCs. Hypoxia significantly increased mRNA expression of VEGF by HD and SSc ADSCs but had no effect on the mRNA expression of pro-fibrotic mediators, ie TGFβ and TGFR. Normal and SSc fibroblast proliferation was significantly reduced in both co-culture systems (p < 0.001) and by treatment with normoxic and hypoxic conditioned medium (CM) (p=0.001 and p=0.002). In the same conditions, mRNA expression and protein secretion of TGF-β1, CTGF and Col I were significantly reduced (p = 0.003, p =0.02, p=0.04). These results were confirmed when normal and SSc fibroblasts were cultured in the presence of ADSCs normoxic and hypoxic CM (p=0.02 and p=0.01). Furthermore, a significant increase in mRNA expression and production of VEGF was observed in SSc fibroblasts cultured in the presence of normoxic and hypoxic CM (p = 0.002 and p< 0.0001, respectively).Conclusion:We found that treatment with the medium from normoxic and hypoxic preconditioned ADSCs has an anti-fibrotic effect through both the inhibition of fibroblast proliferation and key mediators of fibrosis. The increased expression of VEGF by SSc fibroblasts in the presence of normoxic and, even more, hypoxic ADSCs CM, suggests that ADSCs can induce a paracrine pro-angiogenic phenotype, even in fibroblasts with a pro-fibrotic signature. Altogether these data show that ADSCs may exert their anti-fibrotic and pro-angiogenetic effects on SSc fibroblasts by the secretion of paracrine factors, partly explaining the mechanisms underlining beneficial clinical results of fat graft in SSc patients.Disclosure of Interests:Nicoletta Del Papa: None declared, Maurizio Lorini: None declared, Vincenzo Carbonelli: None declared, Antonina Minniti: None declared, Francesca Pignataro: None declared, Wanda Maglione: None declared, Gabriele Di Luca: None declared, Nicola Montano: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB
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Dean, Rachael G., Leanne C. Balding, Riccardo Candido, Wendy C. Burns, Zemin Cao, Stephen M. Twigg, and Louise M. Burrell. "Connective Tissue Growth Factor and Cardiac Fibrosis after Myocardial Infarction." Journal of Histochemistry & Cytochemistry 53, no. 10 (June 27, 2005): 1245–56. http://dx.doi.org/10.1369/jhc.4a6560.2005.
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The temporal and spatial expression of transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF) was assessed in the left ventricle of a myocardial infarction (MI) model of injury with and without angiotensin-converting enzyme (ACE) inhibition. Coronary artery ligated rats were killed 1, 3, 7, 28, and 180 days after MI. TGF-β1, CTGF, and procollagen α1(I) mRNA were localized by in situ hybridization, and TGF-β1 and CTGF protein levels by immunohistochemistry. Collagen protein was measured using picrosirius red staining. In a separate group, rats were treated for 6 months with an ACE inhibitor. There were temporal and regional differences in the expression of TGF-β1, CTGF, and collagen after MI. Procollagen α1(I) mRNA expression increased in the border zone and scar peaking 1 week after MI, whereas collagen protein increased in all areas of the heart over the 180 days. Expression of TGF-β1 mRNA and protein showed major increases in the border zone and scar peaking 1 week after MI. The major increases in CTGF mRNA and protein occurred in the viable myocardium at 180 days after MI. Long-term ACE inhibition reduced left ventricular mass and decreased fibrosis in the viable myocardium, but had no effect on cardiac TGF-β1 or CTGF. TGF-β1 is involved in the initial, acute phase of inflammation and repair after MI, whereas CTGF is involved in the ongoing fibrosis of the heart. The antifibrotic benefits of captopril are not mediated through a reduction in CTGF.
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Qi, W., S. Twigg, X. Chen, T. S. Polhill, P. Poronnik, R. E. Gilbert, and C. A. Pollock. "Integrated actions of transforming growth factor-β1 and connective tissue growth factor in renal fibrosis." American Journal of Physiology-Renal Physiology 288, no. 4 (April 2005): F800—F809. http://dx.doi.org/10.1152/ajprenal.00179.2004.
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Matrix accumulation in the renal tubulointerstitium is predictive of a progressive decline in renal function. Transforming growth factor-β1 (TGF-β1) and, more recently, connective tissue growth factor (CTGF) are recognized to play key roles in mediating the fibrogenic response, independently of the primary renal insult. Further definition of the independent and interrelated effects of CTGF and TGF-β1 is critical for the development of effective antifibrotic strategies. CTGF (20 ng/ml) induced fibronectin and collagen IV secretion in primary cultures of human proximal tubule cells (PTC) and cortical fibroblasts (CF) compared with control values ( P < 0.005 in all cases). This effect was inhibited by neutralizing antibodies to either TGF-β or to the TGF-β type II receptor (TβRII). TGF-β1 induced a greater increase in fibronectin and collagen IV secretion in both PTC ( P < 0.01) and CF ( P < 0.01) compared with that observed with CTGF alone. The combination of TGF-β1 and CTGF was additive in their effects on both PTC and CF fibronectin and collagen IV secretion. TGF-β1 (2 ng/ml) stimulated CTGF mRNA expression within 30 min, which was sustained for up to 24 h, with a consequent increase in CTGF protein ( P < 0.05), whereas CTGF had no effect on TGF-β1 mRNA or protein expression. TGF-β1 (2 ng/ml) induced phosphorylated (p)Smad-2 within 15 min, which was sustained for up to 24 h. CTGF had a delayed effect on increasing pSmad-2 expression, which was evident at 24 h. In conclusion, this study has demonstrated the key dependence of the fibrogenic actions of CTGF on TGF-β. It has further uniquely demonstrated that CTGF requires TGF-β, signaling through the TβRII in both PTCs and CFs, to exert its fibrogenic response in this in vitro model.
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Piura, E., J. W. Chapman, A. Lipton, L. Zhu, K. Leitzel, C. F. Wilson, K. I. Pritchard, L. Shepherd, and M. N. Pollak. "Serum 1-OH vitamin D (D) and prognosis of postmenopausal breast cancer (BC) patients: NCIC-CTG MA14 trial." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 534. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.534.
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534 Background: In vitro, D has demonstrated regulatory functions in breast cancer cells and the bone microenvironment. Higher serum D levels were associated in some prior studies with favorable BC prognosis. We previously found that the baseline serum bone resorption marker, beta C-terminal telopeptides of type I collagen (B-CTx), was associated with bone-only first relapse, and that higher levels of insulin secretion as estimated by c-peptide level was associated with reduced event-free survival (EFS). We hypothesized that baseline serum D might be associated with relapse of breast cancer in bone and/or other metastatic sites. Methods: Baseline D was determined for the phase III MA.14 trial of adjuvant tamoxifen (20 mg/day oral for 5 years) ± octreotide (90 mg/month depot injection for 2 years). Stratification was by adjuvant chemotherapy, axillary lymph node status, and hormone receptor status. EFS, time from randomization to recurrence, second malignancy, or death due to any cause, was the primary endpoint. Recurrence-free survival (RFS), time from randomization to recurrence of the primary disease alone, was a secondary endpoint. For both endpoints, step-wise forward multivariate Cox regression adjusted for stratification factors was used to examine the association of D and outcome; a factor was added if p < 0.05. Results: Baseline D levels were available for 607 (91%) patients. As expected, D levels for a population far from the equator varied with month of blood draw (p = 0.007), which gives confidence in assay performance. Continuous D was not associated with RFS of any relapse (p = 0.57), bone only relapse (p = 0.19), bone + other site of relapse (p = 0.73), or all bone relapse types (p = 0.66). D was not associated with EFS (0.43), even when adjusted by season (p = 0.64), level deficiency/insufficiency vs sufficiency/toxicity (p = 0.69), age (p = 0.54), and BMI (p = 0.32). As well, interactions between D and season, age, and BMI were non-significant (respectively, p = 0.90, 0.84, 0.23). Conclusions: D was not associated with EFS or RFS in postmenopausal breast cancer patients in this well controlled hormonal therapy study, a result consistent with some, but not all, studies of this issue. No significant financial relationships to disclose.
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Zheng, Shizhong, and Anping Chen. "Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 5 (May 2006): G883—G893. http://dx.doi.org/10.1152/ajpgi.00450.2005.
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Upon liver injury, quiescent hepatic stellate cells (HSCs), the most relevant cell type for hepatic fibrogenesis, become active and overproduce extracellular matrix (ECM). Connective tissue growth factor (CTGF) promotes ECM production. Overexpression of CTGF during hepatic fibrogenesis is induced by transforming growth factor (TGF)-β. We recently demonstrated that curcumin reduced cell growth and inhibited ECM gene expression in activated HSCs. Curcumin induced gene expression of peroxisome proliferator-activated receptor (PPAR)-γ and stimulated its activity in activated HSCs, which was required for curcumin to suppress ECM gene expression, including αI(I)-collagen. The underlying mechanisms remain largely unknown. The aim of this study was to elucidate the mechanisms by which curcumin suppresses αI(I)-collagen gene expression in activated HSCs. We hypothesize that inhibition of αI(I)-collagen gene expression in HSCs by curcumin is mediated by suppressing CTGF gene expression through attenuating oxidative stress and interrupting TGF-β signaling. The present report demonstrated that curcumin significantly reduced the abundance of CTGF in passaged HSCs and suppressed its gene expression. Exogenous CTGF dose dependently abrogated the inhibitory effect of curcumin. Activation of PPAR-γ by curcumin resulted in the interruption of TGF-β signaling by suppressing gene expression of TGF-β receptors, leading to inhibition of CTGF gene expression. The phytochemical showed its potent antioxidant property by significantly increasing the level of total glutathione (GSH) and the ratio of GSH to GSSG in activated HSCs. De novo synthesis of cellular GSH was a prerequisite for curcumin to interrupt TGF-β signaling and inhibited gene expression of CTGF and αI(I)-collagen in activated HSCs. Taken together, our results demonstrate that inhibition of αI(I)-collagen gene expression by curcumin in activated HSCs results from suppression of CTGF gene expression through increasing cellular GSH contents and interruption of TGF-β signaling. These results provide novel insights into the mechanisms underlying inhibition of HSC activation by curcumin.
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Weng, Lin, Weiling Wang, Xiaohong Su, Yong Huang, Limin Su, Ming Liu, Yi Sun, Baoxue Yang, and Hong Zhou. "The Effect of cAMP-PKA Activation on TGF-β1-Induced Profibrotic Signaling." Cellular Physiology and Biochemistry 36, no. 5 (2015): 1911–27. http://dx.doi.org/10.1159/000430160.
Full textAbstract:
Background: The cAMP-PKA signaling pathway and TGF-β1-dependent fibrosis pathways are of particular importance in ADPKD progression, but the cross-talk between these pathways remains unclear. Therefore, we used an MDCK-cell model and embryonic kidney-cyst model to study the regulatory role of cAMP-PKA signaling in the TGF-β1 induced fibrotic process. Method and Results: Pkd1flox/flox; Ksp-Cre and Pkd1+/+; Ksp-Cre mice were used as an in vivo model. Increased kidney volume, renal cysts formation and up-regulation of the fibrosis-related proteins TGF-β1, connective tissue growth factor (CTGF), and fibronectin (FN) can be observed in Pkd1flox/flox; Ksp-Cre mice. In an embryonic kidneys-cyst model, TGF-β1, FN and collagen type I were highly expressed. Western blotting revealed the obviously up-regulation of TGF-β1, CTGF, FN and collagen type I expression following forskolin treatment in MDCK cells. Selective PKA inhibition with H89 may partially reversed the above effects. Pretreatment with the TGF-β RI kinase inhibitor VI SB431542 suppressed the increased expression of CTGF, FN and collagen type I caused by forskolin. Our data also indicate that forskolin inhibited TGF-β-induced ERK1/2 phosphorylation and FN up-regulation. ERK inhibition useing PD98059 significantly inhibited the expression of CTGF, FN and collagen type I caused by TGF-β1. Conclusions: The cAMP-PKA signaling pathway can directly promote the production of TGF-β1 and/or TGF-β1-dependent fibrogenetic molecules in MDCK cells and embryonic kidney cysts, but when TGF-β1 and its downstream pathways were highly expressed in MDCK cells, cAMP-PKA had a significantly negative effect on TGF-β1 induced p-ERK1/2 and FN expression.
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Tan, Yan, Bing Wang, Joo-Seob Keum, and Ayad A. Jaffa. "Mechanisms through which bradykinin promotes glomerular injury in diabetes." American Journal of Physiology-Renal Physiology 288, no. 3 (March 2005): F483—F492. http://dx.doi.org/10.1152/ajprenal.00165.2004.
Full textAbstract:
In diabetes, mesangial cell proliferation and extracellular matrix expansion are critical components in the development of glomerulosclerosis. We reported that diabetes alters the activity of the kallikrein-kinin system and that these alterations contribute to the development of diabetic nephropathy. The present study examined the influence of streptozotocin-induced diabetes on the renal expression of bradykinin (BK) B2 receptors (B2KR), connective tissue growth factor (CTGF), transforming growth factor-β (TGF-β), and TGF-β type II receptor (TGF-βRII) and assessed the signaling mechanisms through which B2KR activation may promote glomerular injury. Eight weeks after the induction of diabetes, renal mRNA levels of B2KR, CTGF, and TGF-β as well as protein levels of CTGF and TGF-βRII were measured in control (C), diabetic (D), and insulin-treated diabetic (D+I) rats. Renal B2KR and TGF-β mRNA levels expressed relative to β-actin mRNA levels and CTGF and TGF-βRII protein levels were significantly increased in D and D+I rats compared with C rats ( P < 0.03, n = 5). To assess the contribution of B2KR activation on modulating the expression of CTGF, TGF-βRII, and collagen I, mesangial cells (MC) were treated with BK (10−8 M) for 24 h and CTGF and TGF-βRII protein levels were measured by Western blots and collagen I mRNA levels were measured by RT-PCR. A two- to threefold increase in CTGF and TGF-βRII protein levels was observed in response to BK stimulation ( P < 0.001, n = 6). In addition, a marked increase in collagen I mRNA levels was observed in response to BK stimulation. Treatment of MC with BK (10−8 M) for 5 min significantly increased the tyrosine phosphorylation of p60src kinase and of p42/p44 MAPK ( P < 0.05, n = 4). Inhibition of src kinase by PP1 (10 μM) inhibited the increase in p42/p44 MAPK activation in response to BK. Finally, to determine whether BK stimulates CTGF, TGF-βRII, and collagen I expression via activation of MAPK pathways, MC were pretreated with an inhibitor of p42/p44 MAPK (PD-98059) for 45 min, followed by BK (10−8 M) stimulation for 24 h. Selective inhibition of p42/p44 MAPK significantly inhibited the BK-induced increase in CTGF, TGF-βRII, and collagen I levels. These findings are the first to demonstrate that BK regulates the expression of CTGF, TGF-βRII, and collagen I in MC and provide a mechanistic pathway through which B2KR activation may contribute to the development of diabetic nephropathy.
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Wang, Xuan, Xia Li, Li-na Wang, Jing-juan Pan, Xue Yang, and Yang-lin Wei. "Buyang Huanwu Decoction Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats via Downregulation of Related Protein and Gene Expression." Evidence-Based Complementary and Alternative Medicine 2018 (2018): 1–8. http://dx.doi.org/10.1155/2018/9185485.
Full textAbstract:
Little is known about the effects of Buyang Huanwu decoction on pulmonary fibrosis. Herein, 144 healthy SD rats were randomly divided into six groups: blank control group (B), model control group (M), positive medicine control group (Mp), and high-, moderate-, and low-dose Buyang Huanwu decoction groups (Hd, Md, and Ld). A pulmonary fibrosis model was established by endotracheal injection of bleomycin. On the second day of modeling, the corresponding saline, methylprednisolone suspension, and the three doses of Buyang Huanwu decoction were used to treat the 6 groups of rats by intragastric administration for 7, 14, and 28 consecutive days. After 7, 14, and 28 days of treatment, the mRNA expression of CTGF and AKT, the protein level of CTGF, p-AKT, and collagen types I and III were tested. Finally, we found that the serum collagen type I and III level in Hd, Md, and Ld rats on the 14th and 28th day and the collagen type I and III level in Hd rats on 7th day were significantly lower than in M rats (P<0.01). The protein level of p-AKT and CTGF in Hd and Md rats on the 7th and 14th days and the protein level of p-AKT in Hd rats on the 28th day were lower than in M rats (P<0.01, P<0.05). The level of CTGF mRNA in Hd, Md, and Ld rats and the level of AKT mRNA in Hd and Md rats on the 7th, 14th, and 28th days and the expression level of AKT mRNA in Ld rats on the 14th and 28th days were significantly lower than in M rats (P<0.01). The study suggests that Buyang Huanwu decoction alleviated pulmonary fibrosis of rats by improvement of lung tissue morphology, low level of serum collagen types I and III, and the reduced expression of CTGF and p-AKT protein, which might be a result of its downregulated expression of CTGF and AKT mRNA levels.
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Qi, Weier, Xinming Chen, Tania S. Polhill, Siska Sumual, Stephen Twigg, Richard E. Gilbert, and Carol A. Pollock. "TGF-β1 induces IL-8 and MCP-1 through a connective tissue growth factor-independent pathway." American Journal of Physiology-Renal Physiology 290, no. 3 (March 2006): F703—F709. http://dx.doi.org/10.1152/ajprenal.00254.2005.
Full textAbstract:
Transforming growth factor-β1 (TGF-β1) functions as an important immunomodulatory cytokine in human kidney. Evidence suggests that connective tissue growth factor (CTGF) is an important downstream mediator of the profibrotic effects of TGF-β1. However, the role of CTGF in TGF-β1-induced chemokine production remains unknown. This study was undertaken to determine whether CTGF is involved in mediating TGF-β1-induced chemokine production in renal proximal tubular (HK-2) cells. Interleukin-8 (IL-8) and macrophage chemoattractant protein-1 (MCP-1) were measured. TGF-β1 induced an increase in IL-8 and MCP-1 (both P < 0.05) compared with control levels. CTGF was effectively silenced using small interference RNA (siRNA) in HK-2 cells. RT-PCR and real-time PCR confirmed a 94% reduction in CTGF mRNA. In the CTGF-silenced cells, TGF-β1-stimulated IL-8 and MCP-1 secretion was not altered compared with control cells. Similarly, basal secretion of IL-8 and MCP-1 was not changed in CTGF-silenced cells. The direct effect of CTGF (20, 200, and 400 ng/ml) on IL-8 and MCP-1 was assessed at 24-, 48-, and 72-h time points and no stimulation was observed. Our studies further demonstrate that in the CTGF gene-silenced cells, CTGF partially mediates TGF-β1-induced fibronectin and collagen IV secretion. These data suggest that TGF-β1 induced IL-8 and MCP-1 via CTGF-independent pathway. TGF-β mediates both fibrosis and chemokine production in the proximal tubule of the kidney. However, CTGF plays a more specific role as a downstream mediator of TGF-β1-induced fibrosis.
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Vial, Cecilia, Jaime Gutiérrez, Cristian Santander, Daniel Cabrera, and Enrique Brandan. "Decorin Interacts with Connective Tissue Growth Factor (CTGF)/CCN2 by LRR12 Inhibiting Its Biological Activity." Journal of Biological Chemistry 286, no. 27 (March 23, 2011): 24242–52. http://dx.doi.org/10.1074/jbc.m110.189365.
Full textAbstract:
Fibrotic disorders are the end point of many chronic diseases in different tissues, where an accumulation of the extracellular matrix occurs, mainly because of the action of the connective tissue growth factor (CTGF/CCN2). Little is known about how this growth factor activity is regulated. We found that decorin null myoblasts are more sensitive to CTGF than wild type myoblasts, as evaluated by the accumulation of fibronectin or collagen III. Decorin added exogenously negatively regulated CTGF pro-fibrotic activity and the induction of actin stress fibers. Using co-immunoprecipitation and in vitro interaction assays, decorin and CTGF were shown to interact in a saturable manner with a Kd of 4.4 nm. This interaction requires the core protein of decorin. Experiments using the deletion mutant decorin indicated that the leucine-rich repeats (LRR) 10–12 are important for the interaction with CTGF and the negative regulation of the cytokine activity, moreover, a peptide derived from the LRR12 was able to inhibit CTGF-decorin complex formation and CTGF activity. Finally, we showed that CTGF specifically induced the synthesis of decorin, suggesting a mechanism of autoregulation. These results suggest that decorin interacts with CTGF and regulates its biological activity.