Transcriptional Regulation of Tissue- and Urokinase-type Plasminogen Activator Genes by Thrombin in Human Fetal Lung Fibroblasts

Hayakawa, Yumiko; Tazawa, Shigeki; Ishikawa, T.; Niiya, Kenji; Sakuragawa, Nobuo

doi:10.1055/s-0038-1649801

Cited by 14 publications

(11 citation statements)

References 42 publications

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“…Several groups of investigators reported the ability of thrombin to cause an increased PAI-1 gene expression in a variety of cell lines, potentially reducing the activity of the fibrinolytic system (58,59). However, thrombin was reported to increase also the expression of plasminogen activators (60,61). Indeed, in this study we observed that thrombin induced u-PA gene expression in proximal tubular cells, respectively, confirming previous observations.…”

Section: Discussionsupporting

confidence: 92%

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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ABSTRACT. An increasing body of evidence suggests that proteases may play a key role in the pathogenesis of tissue fibrosis. Protease-activated receptor-2 (PAR-2) is cleaved and activated by trypsin-like proteolytic enzymes, including tryptase and activated coagulation factor X (FXa). Both these soluble mediators have been demonstrated, directly or indirectly, at the interstitial level in progressive renal diseases, including IgA nephropathy (IgAN). PAR-2 mRNA and protein levels were investigated by RT-PCR and immunohistochemistry, respectively, in 17 biopsies from IgAN patients and 10 normal kidneys. PAR-2 expression was also evaluated, by RT-PCR and western blotting, in cultured human mesangial and proximal tubular cells. Finally, gene expression of plasminogen activator inhibitor-1 (PAI-1) and TGF-β, two powerful fibrogenic factors, was evaluated in FXa-, trypsin-, and PAR-2 activating peptide-stimulated human proximal tubular cells by Northern blot. In normal kidneys, PAR-2 gene expression was barely detectable, whereas in IgAN biopsies the mRNA levels for this protease receptor were strikingly increased and directly correlated with the extent of interstitial fibrosis. Immunohistochemical staining demonstrated that PAR-2 protein expression in IgAN biopsies was mainly localized in the proximal tubuli and within the interstitial infiltrate. Proximal tubular cells in culture expressed PAR-2. Activation of this receptor by FXa in tubular cells induced a striking increase in intracellular calcium concentration. In addition, incubation of both cell lines with trypsin, FXa, or PAR-2 activating peptide caused a marked upregulation of PAI-1 gene expression that was not counterbalanced by an increased expression of plasminogen activators. Finally, PAR-2 activation induced a significant upregulation of TGF-β gene and protein expression in both mesangial and tubular cells. On the basis of our data, we can suggest that PAR-2 expressed by renal resident cells and activated by either mast cell tryptase or FXa may induce extracellular matrix deposition modifying the PAI-1/PA balance and inducing TGF-β expression. These molecular mechanisms may underlie interstitial fibrosis in IgAN. E-mail: g.grandaliano@nephro.uniba.it

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Section: Discussionsupporting

confidence: 92%

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Grandaliano

Pontrelli²,

Cerullo³

et al. 2003

Journal of the American Society of Nephrology

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“…9). In addition, it has been reported that thrombin increases the level of PAI-1 in other cellular systems, including smooth muscle cells, endothelial cells, epithelial cells, and lung fibroblasts (Dichek and Quertermous, 1989;Hayakawa et al, 1995;Noda-Heiny et al, 1993). Thus, the present work demonstrates that the stimulation of PAI-1 by thrombin also occurs in nervous system cells, and this mechanism may have a role in OEG-dependent neuroregeneration.…”

Section: Discussionsupporting

confidence: 68%

“…Thrombin signals through PAR-1, and TM is an allosteric modulator of thrombin that attenuates this signaling. In addition, it has been shown in several cell systems that thrombin regulates the expression of PAI-1 (Dichek and Quertermous, 1989;Hackett and Campochiaro, 1993;Hayakawa et al, 1995;Noda-Heiny et al, 1993). Moreover, inhibitors of plasminogen activators, including PAI-1, have been implicated in neurite outgrowth (Leprince et al, 1991;Pittman et al, 1989;Sumi et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Expression of plasminogen activator inhibitor-1 by olfactory ensheathing glia promotes axonal regeneration

Simón

Martín‐Bermejo

Gallego-Hernández

et al. 2011

Glia

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Olfactory ensheathing glia (OEG) cells are known to facilitate repair following axotomy of adult neurons, although the molecular mechanisms involved are not fully understood. We previously identified plasminogen activator inhibitor-1 (PAI-1), proteinase-activated receptor-1 (PAR-1), and thrombomodulin (TM) as candidates to regulate rat OEG-dependent axonal regeneration. In this study, we have validated the involvement of these proteins in promoting axonal regeneration by immortalized human OEGs. We studied the effect of silencing these proteins in OEGs on their capacity to promote the regeneration of severed adult retinal ganglion cells (RGCs) axons. Our results support the role of glial PAI-1 as a downstream effector of PAR-1 in promoting axon regeneration. In contrast, we found that TM inhibits OEG induced-axonal regeneration. We also assessed the signaling pathways downstream of PAR-1 that might modulate PAI-1 expression, observing that specifically inhibiting Gα(i), Rho kinase, or PLC and PKC downregulated the expression of PAI-1 in OEGs, with a concomitant reduction in OEG-dependent axon regeneration in adult RGCs. Our findings support an important role for the thrombin system in regulating adult axonal regeneration by OEGs.

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“…In addition, it has been shown that thrombin in general elevates the level of PAI-1 mRNA in various cell types including umbilical vein endothelial cells, 23,24) umbilical vein smooth muscle cells, 22) aortic smooth muscle cells, 25,26) renal mesangial cells, 27) retinal epithelial cells, 28) endometrial stromal cells, 29) peritoneal mesothelial cells 30) and fetal lung fibroblasts. 31) However, as shown in this study, thrombin increased the secretion of PAI-1 without changes in the level of PAI-1 mRNA in human microvascular pericytes and endothelial cells. The posttranscriptional regulation of PAI-1 synthesis may also be unique to brain microvascular cells.…”

Section: Discussionsupporting

confidence: 50%

Selective Promotion of Plasminogen Activator Inhibitor-1 Secretion by Activation of Proteinase-Activated Receptor-1 in Cultured Human Brain Microvascular Pericytes: Comparison with Endothelial Cells

Yamamoto

Sugato

Fujiwara

et al. 2005

Biological & Pharmaceutical Bulletin

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Fibrinolysis is the phenomenon by with plasmin degrades fibrin. The fibrinolytic activity depends on the balance between tissue-and urokinase-type plasminogen activators (t-PA and u-PA, respectively) and plasminogen activator inhibitor-1 (PAI-1).1) Both t-PA and u-PA convert plasminogen to plasmin that degrades fibrin. On the other hand, PAI-1 is a common inhibitor of t-PA and u-PA; a large part of PAI-1 in the liquid phase is a latent form, 2) and the remainding active form inhibits t-PA and u-PA by forming inactive complexes.3)The fibrinolytic proteins are expressed in vascular composing cells, and regulation of the synthesis and secretion are different among cell types and origins. 4,5) Microvessels are composed of endothelial cells that cover the inner surface in a monolayer and pericytes that wrap around and along endothelial cells.6) The regulation of fibrinolysis in vascular endothelial cells and pericytes is important for the removal of intravascular thrombi and the maintenance of hemostasis, respectively, in microvessels. Since cerebrovascular accident is a serious public health problem in advanced countries including Japan, it appears to be important to clarify the regulation of fibrinolysis mediated by brain microvascular endothelial cells and pericytes. Immunohistochemical studies have shown that fibrinolytic proteins such as t-PA and u-PA are expressed in brain microvascular endothelium in vivo, 7) although the regulation of fibrinolytic protein synthesis has been incompletely understood. Furthermore, little is known about the expression of fibrinolytic proteins and its regulation in pericytes.Thrombin not only converts fibrinogen to fibrin in the blood coagulation-fibrinolytic system but also regulates vascular cell functions. Proteinase regulates the synthesis and secretion of fibrinolytic proteins in vascular endothelial cells 8,9) by activation of proteinase-activated receptor-1 (PAR-1).10,11) Thrombin stimulation occurs in different patterns depending on the origin of the cells. For example, thrombin upregulates the expression of t-PA, u-PA, and PAI-1 in both cultured renal 12) and foreskin 13) microvascular endothelial cells. At that time, the activity of t-PA is enhanced in the renal endothelial cells but suppressed in the foreskin endothelial cells. It has been shown that thrombin upregulates the expression of fibrinolytic proteins in cultured human brain microvascular endothelial cells 14) ; however, the subsequent change in fibrinolytic activity is unknown.The purpose of the present study is to determine the plasminogen activator activity and the expression of fibrinolytic proteins in cultured human brain microvascular pericytes and endothelial cells after exposure to thrombin. We found that thrombin increases the secretion of t-PA, u-PA, and PAI-1, resulting in an enhancement of plasminogen activator activity in endothelial cells, whereas proteinase increased the secretion only of PAI-1, resulting in suppression of plasminogen activator activity in pericytes. MATERIALS AND METHODS Materia...

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Transcriptional Regulation of Tissue- and Urokinase-type Plasminogen Activator Genes by Thrombin in Human Fetal Lung Fibroblasts

Cited by 14 publications

References 42 publications

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Protease-Activated Receptor-2 Expression in IgA Nephropathy

Expression of plasminogen activator inhibitor-1 by olfactory ensheathing glia promotes axonal regeneration

Selective Promotion of Plasminogen Activator Inhibitor-1 Secretion by Activation of Proteinase-Activated Receptor-1 in Cultured Human Brain Microvascular Pericytes: Comparison with Endothelial Cells

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