JNK-dependent AP-1 activation is required for aristolochic acid-induced TGF-β1 synthesis in human renal proximal epithelial cells

Chronic aristolochic acid nephropathy (CAAN) is a chronic and progressive tubulointerstitial nephropathy characterized by extensive interstitial fibrosis. Aristolochic acid (AA) could induce overexpression of transforming growth factor-β1 (TGF-β1) in a human renal proximal tubule epithelial cells line (HKC), which has been implicated in the pathogenesis of CAAN. The present studies in HKC cells showed 1) AA could activate JNK in time- and dose-dependent manners and JNK inhibitor SP600125 could inhibit AA-induced TGF-β1 promoter activity and TGF-β1 synthesis; 2) AA-induced JNK activation and TGF-β1 synthesis were significantly inhibited by kinase-inactive mutants of MEKK4, MKK4, or MKK7; 3) AA could upregulate luciferase activity derived by a wild-type TGF-β1 promoter, but not by an AP-1 binding-deficient TGF-β1 promoter; and 4) AA could upregulate expression of c-Fos, phospho-c-Jun, and phospho-ATF2. The above data suggest AA-induced TGF-β1 overexpression in HKC cells may be mainly mediated by the JNK signaling pathway. Both the upstream kinases of JNK including MEKK4, MKK4, and MKK7, and the downstream transcription factor of JNK, AP-1, may also participate in this process.

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Studies on the Biological Effects of Ozone: 10. Release of Factors from Ozonated Human Platelets

Mediators of Inflammation ◽

10.1080/09629359990360 ◽

1999 ◽

Vol 8 (4-5) ◽

pp. 205-209 ◽

Cited By ~ 36

Author(s):

G. Valacchi ◽

Velio Bocci

Keyword(s):

Platelet Aggregation ◽

Growth Factor ◽

Transforming Growth Factor ◽

Platelet Rich Plasma ◽

Biological Effects ◽

Transforming Growth Factor Β1 ◽

Human Platelets ◽

Dependent Manner ◽

Dose Dependent ◽

Tgf Β1

In a previous work we have shown that heparin, in the presence of ozone (O3), promotes a dose-dependent platelet aggregation, while after Ca2+chelation with citrate, platelet aggregation is almost negligible. These results led us to think that aggregation may enhance the release of platelet components. We have here shown that indeed significantly higher amount of platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1) and interleukin-8(IL-8) are released in a dose-dependent manner after ozonation of heparinised platelet-rich plasma samples. These findings may explain the enhanced healing of torpid ulcers in patients with chronic limbischemia treated with O3autohaemoteraphy (O3-AHT).

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Transforming growth factor-β1 modulates the expression of vascular endothelial growth factor by osteoblasts

AJP Cell Physiology ◽

10.1152/ajpcell.1999.277.4.c628 ◽

1999 ◽

Vol 277 (4) ◽

pp. C628-C637 ◽

Cited By ~ 130

Author(s):

Pierre B. Saadeh ◽

Babak J. Mehrara ◽

Douglas S. Steinbrech ◽

Matthew E. Dudziak ◽

Joshua A. Greenwald ◽

...

Keyword(s):

Growth Factor ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Vascular Endothelial ◽

Vegf Expression ◽

Vegf Mrna ◽

Endothelial Growth Factor ◽

Dose Dependent ◽

Tgf Β1 ◽

Vegf Protein

Angiogenesis is essential to both normal and pathological bone physiology. Vascular endothelial growth factor (VEGF) has been implicated in angiogenesis, whereas transforming growth factor-β1 (TGF-β1) modulates bone differentiation, matrix formation, and cytokine expression. The purpose of this study was to investigate the relationship between TGF-β1 and VEGF expression in osteoblasts and osteoblast-like cells. Northern blot analysis revealed an early peak of VEGF mRNA (6-fold at 3 h) in fetal rat calvarial cells and MC3T3-E1 osteoblast-like cells after stimulation with TGF-β1 (2.5 ng/ml). The stability of VEGF mRNA in MC3T3-E1 cells was not increased after TGF-β1 treatment. Actinomycin D inhibited the TGF-β1-induced peak in VEGF mRNA, whereas cycloheximide did not. Blockade of TGF-β1 signal transduction via a dominant-negative receptor II adenovirus significantly decreased TGF-β1 induction of VEGF mRNA. Additionally, TGF-β1 induced a dose-dependent increase in VEGF protein expression by MC3T3-E1 cells ( P < 0.01). Dexamethasone similarly inhibited VEGF protein expression. Both TGF-β1 mRNA and VEGF mRNA were concurrently present in rat membranous bone, and both followed similar patterns of expression during rat mandibular fracture healing (mRNA and protein). In summary, TGF-β1-induced VEGF expression by osteoblasts and osteoblast-like cells is a dose-dependent event that may be intimately related to bone development and fracture healing.

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Abstract 230: Cartilage Intermediate Layer Protein-1 Attenuates Pressure Overload-induced Cardiac Fibrosis by Targeting Transforming Growth Factor-β1

Circulation Research ◽

10.1161/res.117.suppl_1.230 ◽

2015 ◽

Vol 117 (suppl_1) ◽

Author(s):

Li Li ◽

Cheng-Lin Zhang ◽

Dan Wu ◽

Li-Ling Wu

Keyword(s):

Growth Factor ◽

Intermediate Layer ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Nuclear Translocation ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Pressure Overload ◽

Transforming Growth Factor Β1 ◽

Tgf Β1

Background: Cartilage intermediate layer protein-1 (CILP-1), a monomeric extracellular matrix glycoprotein expressed mainly in the middle zones of articular cartilage, interacts directly with transforming growth factor-β1 (TGF-β1). Recent studies showed that CILP-1 was upregulated in the heart tissue following cardiac ischemia reperfusion injury. However, the role of CILP-1 in pathological cardiac remodeling is poorly defined. Aims: To explore the effect of CILP-1 on myocardial interstitial fibrosis and reveal the possible molecular mechanism. Methods and Results: We found that CILP-1 was mainly expressed in mouse cardiac fibroblasts (CFs) by using western blot analysis and immunofluorescence. Myocardial expression of CILP-1 was upregulated in mice subjected to transverse aortic constriction (TAC) for 2, 4, and 8 weeks. AAV-9-mediated delivery of CILP-1 into mice increased the binding of CILP-1 with TGF-β1, attenuated interstitial fibrosis, and improved cardiac function. In cultured adult mouse CFs, CILP-1 overexpression inhibited myofibroblast differentiation and expression of profibrotic molecules induced by TGF-β1. Furthermore, CILP-1 attenuated TGF-β1-induced Smad3 phosphorylation and nuclear translocation. Conclusions: CILP-1 alleviates pressure overload-induced cardiac fibrosis and dysfunction. CILP-1 exerts its anti-fibrotic effect through targeting TGF-β1 signaling. This study will offer a new therapeutic strategy for preventing and treating myocardial interstitial remodeling.

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Proteomics of transforming growth factor β1 (TGF β1) signaling in 184A1 human breast epithelial cells suggests the involvement of casein kinase 2α in TGF β1-dependent p53 phosphorylation at Ser392

Experimental Oncology ◽

10.32471/exp-oncology.2312-8852.vol-41-no-4.13853 ◽

2019 ◽

Vol 41 (4) ◽

Author(s):

H. Woksepp ◽

◽

R.K.R. Saini ◽

O. Zakharchenko ◽

A. Gautier ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Casein Kinase ◽

Human Breast ◽

Breast Epithelial Cells ◽

Breast Epithelial ◽

Human Breast Epithelial Cells ◽

Tgf Β1

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Macrophage-specific deletion of transforming growth factor-β1 does not prevent renal fibrosis after severe ischemia-reperfusion or obstructive injury

AJP Renal Physiology ◽

10.1152/ajprenal.00624.2012 ◽

2013 ◽

Vol 305 (4) ◽

pp. F477-F484 ◽

Cited By ~ 40

Author(s):

Sarah C. Huen ◽

Gilbert W. Moeckel ◽

Lloyd G. Cantley

Keyword(s):

Growth Factor ◽

Kidney Disease ◽

Renal Fibrosis ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Transforming Growth Factor Β1 ◽

Late Time ◽

Tgf Β1

Macrophage infiltration is a prominent feature of the innate immune response to kidney injury. The persistence of macrophages is associated with tubulointerstitial fibrosis and progression of chronic kidney disease. Macrophages are known to be major producers of transforming growth factor-β1 (TGF-β1), especially in the setting of phagocytosis of apoptotic cells. TGF-β1 has long been implicated as a central mediator of tissue scarring and fibrosis in many organ disease models, including kidney disease. In this study, we show that homozygous deletion of Tgfb1 in myeloid lineage cells in mice heterozygous for Tgfb1 significantly reduces kidney Tgfb1 mRNA expression and Smad activation at late time points after renal ischemia-reperfusion injury. However, this reduction in kidney Tgfb1 expression and signaling results in only a modest reduction of isolated fibrosis markers and does not lead to decreased interstitial fibrosis in either ischemic or obstructive injury models. Thus, targeting macrophage-derived TGF-β1 does not appear to be an effective therapy for attenuating progressive renal fibrosis after kidney injury.

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Heterozygous knockout of transforming growth factor-β1 protects Dahl S rats against high salt-induced renal injury

Physiological Genomics ◽

10.1152/physiolgenomics.00119.2012 ◽

2013 ◽

Vol 45 (3) ◽

pp. 110-118 ◽

Cited By ~ 14

Author(s):

Chun Cheng Andy Chen ◽

Aron M. Geurts ◽

Howard J. Jacob ◽

Fan Fan ◽

Richard J. Roman

Keyword(s):

Blood Pressure ◽

Growth Factor ◽

Systolic Blood Pressure ◽

Transforming Growth Factor ◽

Interstitial Fibrosis ◽

Transforming Growth Factor Β1 ◽

High Salt ◽

Glomerular Injury ◽

Protein Excretion ◽

Tgf Β1

The present study employed a zinc-finger nuclease strategy to create heterozygous knockout (KO) rats for the transforming growth factor-β1 ( Tgfb1) gene on the Dahl SS/Jr genetic background (TGF-β1+/− Dahl S). Intercrossing TGF-β1+/− rats did not produce any homozygous KO rats (66.4% +/−, 33.6% +/+), indicating that the mutation is embryonic lethal. Six-week-old wild-type (WT) littermates and TGF-β1+/− Dahl S rats were fed a 0.4% (low salt, LS) or 8% NaCl (high salt, HS) diet for 5 wk. Renal cortical expression of TGF-β1, urinary TGF-β1 excretion, proteinuria, glomerular injury and tubulointerstitial fibrosis, and systolic blood pressure were similar in WT and TGF-β1+/− Dahl S rats maintained on the LS diet. The expression and urinary excretion of TGF-β1 increased to a greater extent in WT than in TGF-β1+/−Dahl S rats fed an HS diet for 1 wk. Systolic blood pressure rose by the same extent to 235 ± 2 mmHg in WT and 239 ± 4 mmHg in TGF-β1+/− Dahl S rats fed a HS diet for 5 wk. However, urinary protein excretion was significantly lower in TGF-β1+/− Dahl S than in the WT animals. The degree of glomerular injury and renal cortical and outer medullary fibrosis was markedly less in TGF-β1+/− than in WT rats. These findings suggest that the loss of one copy of the TGF-β1 gene blunts the increase in renal TGF-β1 protein expression and slows the progression of proteinuria, glomerulosclerosis, and renal interstitial fibrosis in Dahl S rats fed an HS diet independently of changes in blood pressure.

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MicroRNA-744 Inhibits Proliferation of Bronchial Epithelial Cells by Regulating Smad3 Pathway via Targeting Transforming Growth Factor-β1 (TGF-β1) in Severe Asthma

Medical Science Monitor ◽

10.12659/msm.912412 ◽

2019 ◽

Vol 25 ◽

pp. 2159-2168 ◽

Cited By ~ 8

Author(s):

Han Huang ◽

Hongxia Lu ◽

Lihong Liang ◽

Yueli Zhi ◽

Beibei Huo ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Severe Asthma ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Bronchial Epithelial Cells ◽

Bronchial Epithelial ◽

Tgf Β1

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Smad and p38-MAPK signaling mediates apoptotic effects of transforming growth factor-β1 in human airway epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00044.2004 ◽

2004 ◽

Vol 287 (3) ◽

pp. L515-L524 ◽

Cited By ~ 27

Author(s):

Nidhi S. Undevia ◽

Delbert R. Dorscheid ◽

Bertha A. Marroquin ◽

Wendy L. Gugliotta ◽

Roberta Tse ◽

...

Keyword(s):

Growth Factor ◽

Epithelial Cells ◽

Protective Effect ◽

P38 Mapk ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Smad Pathway ◽

Tgf Β1

Transforming growth factor-β1 (TGF-β1) belongs to a family of multifunctional cytokines that regulate a variety of biological processes, including cell differentiation, proliferation, and apoptosis. The effects of TGF-β1 are cell context and cell cycle specific and may be signaled through several pathways. We examined the effect of TGF-β1 on apoptosis of primary human central airway epithelial cells and cell lines. TGF-β1 protected human airway epithelial cells from apoptosis induced by either activation of the Fas death receptor (CD95) or by corticosteroids. This protective effect was blocked by inhibition of the Smad pathway via overexpression of inhibitory Smad7. The protective effect is associated with an increase in the cyclin-dependent kinase inhibitor p21 and was blocked by the overexpression of key gatekeeper cyclins for the G1/S interface, cyclins D1 and E. Blockade of the Smad pathway by overexpression of the inhibitory Smad7 permitted demonstration of a TGF-β-mediated proapoptotic pathway. This proapoptotic effect was blocked by inhibition of the p38 MAPK kinase signaling with the inhibitor SB-203580 and was associated with an increase in p38 activity as measured by a kinase assay. Here we demonstrate dual signaling pathways involving TGF-β1, an antiapoptotic pathway mediated by the Smad pathway involving p21, and an apoptosis-permissive pathway mediated in part by p38 MAPK.

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