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- Title
jun-N-terminal kinase regulates thrombin-induced PAI-1 gene expression in proximal tubular epithelial cells.
- Authors
Pontrelli, Paola; Ranieri, Elena; Ursi, Michele; Ghosh-Choudhury, Goutham; Gesualdo, Loreto; Schena, Francesco Paolo; Grandaliano, Giuseppe
- Abstract
jun-N-terminal kinase regulates thrombin-induced PAI-1 gene expression in proximal tubular epithelial cells. Background. Interstitial activation of the coagulation cascade is a common finding in acute and chronic tubulointerstitial damage. We previously demonstrated that thrombin may induce proximal tubular epithelial cells (PTEC) proliferation and regulate, through plasminogen activator inhibitor (PAI)-1 and urokinase-type plasminogen activator (u-PA), their profibrotic activity. The signaling pathways leading to these effects are still unknown. The PAI-1 promoter contains several activator protein-1 (AP-1) consensus sequences. AP-1 activation is induced by different agonists through jun-N-terminal kinase (JNK). Thus, we investigated the role of the JNK-AP-1 axis on thrombin-induced PAI-1 and u-PA expression in immortalized PTEC and its modulation by PKC and src, two key signaling enzymes. Methods. JNK and src activation was investigated by Western blotting, PAR-1 cellular surface expression by flow cytometry, PAI-1 and u-PA gene expression by Northern blotting, AP-1 activation by transient transfection, and DNA synthesis by 3H-thymidine uptake. Results. Thrombin and PMA induced a time-dependent increase of JNK phosphorylation in immortalized PTEC that was inhibited by PKC down-regulation. Both thrombin and PMA caused AP-1 activation, significantly reduced by src inhibition. Phorbol 12-myristate 13-acetate (PMA), indeed, induced an increase in src phosphorylation. Both PMA- and thrombin-stimulated PAI-1 gene expression was abolished by JNK, protein kinase C (PKC), and src inhibition, and this effect was regulated at the trascriptional level. PKC, but not src or JNK inhibition, abolished thrombin-elicited u-PA expression.
- Subjects
THROMBIN; EPITHELIAL cells; GENE expression; GENETIC regulation; HEMOSTATICS; GENES
- Publication
Kidney International, 2004, Vol 65, Issue 6, p2249
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1111/j.1523-1755.2004.00644.x