scholarly journals Krüppel-Like Factor 4 Inhibits the Transforming Growth Factor-β1-Promoted Epithelial-to-Mesenchymal Transition via Downregulating Plasminogen Activator Inhibitor-1 in Lung Epithelial Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Fang Sun ◽  
Ke Hu
Keyword(s):  
Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Plasminogen Activator Inhibitor ◽  
Lung Epithelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Mesenchymal Transition ◽  
Lung Epithelial ◽  
Activator Inhibitor ◽  
Pai 1

Transforming growth factor-β(TGF-β) signaling and TGF-β-promoted epithelial-to-mesenchymal transition (EMT) have been postulated to be the common pathway causing pulmonary fibrosis. However, the up- or downstreaming markers of TGF-β-induced EMT still need to be further recognized. In the present study, we investigated the regulation on Krüppel-like factor 4 (KLF-4) and plasminogen activator inhibitor-1 (PAI-1) by TGF-βin the murine lung epithelial LA-4 cells and then examined the regulation of both markers in the TGF-β-induced EMT by the PAI-1 knockdown or the KLF-4 overexpression. Our study indicated that TGF-βinduced EMT in mouse LA-4 lung epithelial cells via reducing E-cadherin, while promoting Collagen I andα-SMA. And PAI-1 was upregulated, whereas KLF-4 was downregulated in the TGF-β-induced EMT model in LA-4 cells. Moreover, the siRNA-mediated PAI-1 knockdown inhibited the TGF-β-induced EMT, whereas the adenovirus-medicated KLF-4 overexpression markedly reduced the PAI-1 expression and inhibited the TGF-β-induced EMT in LA-4 cells. In conclusion, our study confirmed the downregulation of KLF-4 in the TGF-β-induced EMT in LA-4 cells. And the KLF-4 overexpression significantly reduced the TGF-β-induced PAI-1 and thus inhibited the TGF-β-induced EMT in mouse lung epithelial LA-4 cells. It implies that KLF-4 might be a promising target for effective control of the pulmonary fibrosis.

Abstract 1331: Myocardial Function Alterations Correlate to Cardiac Fibrosis and Upregulation of Profibrotic Signaling in Plasminogen Activator Inhibitor-1 Deficient Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
William Bradham ◽  
Linda Gleaves ◽  
Mousumi Medda ◽  
Douglas Vaughan
Keyword(s):  
Growth Factor ◽  
Plasminogen Activator ◽  
Cardiac Fibrosis ◽  
Plasminogen Activator Inhibitor ◽  
Rt Pcr ◽  
Plasminogen Activator Inhibitor 1 ◽  
Internal Dimension ◽  
Functional Consequences ◽  
Activator Inhibitor ◽  
Pai 1

Cardiac fibrosis is a common sequelae of cardiac injury and has deleterious functional consequences impacting cardiac filling, function and rhythm. Plasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of tissue fibrosis in mice. To investigate the longitudinal effect of PAI-1 on cardiac structure and function, M-mode echocardiography was employed to examine cardiac function in PAI-1 deficient (PAI-1 −/− ) and wild-type (WT) control mice in four age groups (6,12,18, 24 months). Eighteen month old PAI-1 −/− mice exhibited reduced left ventricular (LV) diastolic internal dimension ( p =0.0118) and a trend towards increased LV posterior wall (LVPW) thickness, compared to WT. Two year old PAI-1 −/− mice showed increased diastolic and systolic LVPW thickness ( p =0.0127 and p =0.0212, respectively), reduced diastolic and systolic LV internal dimension ( p =0.0486 and p =0.0124), but with preserved LV fractional shortening compared to WT. Histological examination of cardiac sections revealed fibrosis on the anterior epicardial surface of the hearts in 18 month old PKO, which in 26 month old mice had become confluent with extensive (10 –17% by area) epicardial, perivascular, and interstitial distribution (compared to none in WT). Real time polymerase chain reaction (RT-PCR) revealed upregulation of transforming growth factor beta (TGF-β) and fibroblast growth factor 2 in PAI-1 −/− compared to WT ( p =0.0234 and p =0.037, respectively). Immunofluoresence confirmed this finding with bright TGF-β staining localized in the media of intra-myocardial arterioles, and phosphorylated SMAD2/3, the downstream TGF-β signaling mediator, in areas of fibrosis. Thoracic aortic cells from aged (18 –24 month) PKO and WT mice were grown in culture, with RT-PCR revealing 4 fold increased TGF-β and 17 fold increased SMAD3 ( p <0.05 for both) RNA levels in PAI-1 −/− , supplying additional evidence for upregulation of a profibrotic TGF-β/SMAD tissue signaling pathway. The present study is one of the first to elucidate some of the functional consequences and relevant molecular signaling pathways related to aging and PAI-1 deficiency mediated cardiac fibrosis.

Transcriptional regulation of plasminogen activator inhibitor-1 expression by insulin-like growth factor-1 via MAP kinases and hypoxia-inducible factor-1 in HepG2 cells

2005 ◽  
Vol 93 (06) ◽  
pp. 1176-1184 ◽  
Author(s):  
Ulrike Möller ◽  
Stephan Herzig ◽  
Trine Fink ◽  
Vladimir Zachar ◽  
Peter Ebbesen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepg2 Cells ◽  
Hypoxia Inducible Factor ◽  
Plasminogen Activator Inhibitor ◽  
Dominant Negative ◽  
Plasminogen Activator Inhibitor 1 ◽  
Protein Levels ◽  
Hypoxia Inducible Factor 1 ◽  
Activator Inhibitor ◽  
Pai 1

SummaryInsulin-like growth factor 1 (IGF-1) and plasminogen activator inhibitor-1 (PAI-1) appear to play a crucial role in a number of processes associated with growth and tissue remodelling. IGF-1 was shown to enhance PAI-1 expression in primary hepatocytes and HepG2 hepatoma cells, but the molecular mechanisms underlying this effect have not been fully elucidated. In this study, we investigated the transcriptional mechanism and the signaling pathway by which IGF-1 mediates induction of PAI-1 expression in HepG2 cells. By using human PAI-1 promoter reporter gene assays we found that mutation of the hypoxia responsive element (HRE), which could bind hypoxia-inducible factor-1 (HIF-1), nearly abolished the induction by IGF-1. We found that IGF-1-induced up-regulation of PAI-1 expression was associated with activation of HIF-1α. Furthermore, IGF-1 enhanced HIF-1α protein levels and HIF-1 DNA-binding to each HRE, E4 and E5 as shown by EMSA. Mutation of the E-boxes, E4 and E5, did not affect the IGF-1-dependent induction of PAI-1 promoter constructs under normoxia but abolished the effect of IGF-1 under hypoxia. Inhibition of either the PI3K by LY294002 or ERK1/2 by U0126 reduced HIF-1α protein levels while both inhibitors together completely abolished the IGF-1 effect on HIF-1α. Remarkably, transfection of HepG2 cells with vectors expressing a dominant-negative PDK1 or the PKB inhibitor, TRB3, did not influence while dominant-negative Raf inhibited the IGF-1 effect on HIF-1α. Thus, IGF-1 activates human PAI-1 gene expression through activation of the PI3-kinase and ERK1/2 via HIF-1α.

scholarly journals Fibroblast-specific plasminogen activator inhibitor-1 depletion ameliorates renal interstitial fibrosis after unilateral ureteral obstruction

2019 ◽  
Vol 34 (12) ◽  
pp. 2042-2050 ◽  
Author(s):  
Lan Yao ◽  
M Frances Wright ◽  
Brandon C Farmer ◽  
Laura S Peterson ◽  
Amir M Khan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Plasminogen Activator ◽  
Ureteral Obstruction ◽  
Interstitial Fibrosis ◽  
Plasminogen Activator Inhibitor ◽  
Unilateral Ureteral Obstruction ◽  
Tubular Epithelium ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Background Plasminogen activator inhibitor-1 (PAI-1) expression increases extracellular matrix deposition and contributes to interstitial fibrosis in the kidney after injury. While PAI-1 is ubiquitously expressed in the kidney, we hypothesized that interstitial fibrosis is strongly dependent on fibroblast-specific PAI-1 (fbPAI-1). Methods Tenascin C Cre (TNC Cre) and fbPAI-1 knockdown (KD) mice with green fluorescent protein (GFP) expressed within the TNC construct underwent unilateral ureteral obstruction and were sacrificed 10 days later. Results GFP+ cells in fbPAI-1 KD mice showed significantly reduced PAI-1 expression. Interstitial fibrosis, measured by Sirius red staining and collagen I western blot, was significantly decreased in fbPAI-1 KD compared with TNC Cre mice. There was no significant difference in transforming growth factor β (TGF-β) expression or its activation between the two groups. However, GFP+ cells from fbPAI-1 KD mice had lower TGF β and connective tissue growth factor (CTGF) expression. The number of fibroblasts was decreased in fbPAI-1 KD compared with TNC Cre mice, correlating with decreased alpha smooth muscle actin (α-SMA) expression and less fibroblast cell proliferation. TNC Cre mice had decreased E-cadherin, a marker of differentiated tubular epithelium, in contrast to preserved expression in fbPAI-1 KD. F4/80-expressing cells, mostly CD11c+/F4/80+ cells, were increased while M1 macrophage markers were decreased in fbPAI-1 KD compared with TNC Cre mice. Conclusion These findings indicate that fbPAI-1 depletion ameliorates interstitial fibrosis by decreasing fibroblast proliferation in the renal interstitium, with resulting decreased collagen I. This is linked to decreased M1 macrophages and preserved tubular epithelium.

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