+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

jun-N-terminal kinase regulates thrombin-induced PAI-1 gene expression in proximal tubular epithelial cells

, : jun-N-terminal kinase regulates thrombin-induced PAI-1 gene expression in proximal tubular epithelial cells. Kidney International 65(6): 2249-2261

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. Finally, JNK inhibition did not influence thrombin-induced proliferation. Conclusion. Our data suggest that thrombin activates the JNK-AP-1 axis in a PKC- and src-dependent manner in PTEC. This axis, necessary for thrombin-stimulated PAI-1 expression, but not for its fibrinolytic and regenerative effect, may represent a therapeutic target in acute and chronic tubulointerstitial damage.


PMID: 15149338

DOI: 10.1111/j.1523-1755.2004.00644.x

Other references

Zverkova, A.S., 1968: The results of administering a suspension of spleen cells in transplantable myelosis. Voprosy Onkologii 14(12): 39-43

Mcbride, C.F., 1969: Spiral grain losses cost B.C. industry $5 million a year. In studies at the Forest Products Laboratory, Vancouver, the lumber value of 14 Douglas Fir and 4 Engelmann Spruce logs with a combination of spiral grain and heart shake was compared with the value of the lumber if the grain had been straight. Th...

Amenta, E.; Miceli, F.; Saviano, M.S.; Lucisano, E., 1979: Clinico-radiological studies of a case of complicated cystic pneumopathy. Annali Italiani di Chirurgia 51(4): 469-474

Waxman, A.R.; Arout, C.; Caldwell, M.; Dahan, A.; Kest, B., 2009: Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice. Although mu-receptor opioids are clinically important analgesics, they can also paradoxically cause hyperalgesia independently of opioid receptor activity, presumably via the action of neuroexcitatory glucoronide metabolites. However, it is unknow...

Jarvis, E.D., 2016: Listening in. Zebra finches communicate with each other in ways that are more complex than previously thought.

Kadekaro, A.Luisa.; Andrade, L.N.S.; Floeter-Winter, L.M.; Rollag, M.D.; Virador, V.; Vieira, W.; Castrucci,, 2004: MT-1 melatonin receptor expression increases the antiproliferative effect of melatonin on S-91 murine melanoma cells. Melatonin, a derivative of tryptophan that is present in all vertebrates, was first described in bovine pineal gland. It is known that melatonin is a highly conserved molecule, present also in unicellular organisms and plants. Several effects of m...

Tao, C-Yuan.; Liu, Z-Hua.; Li, X-Hong.; Du, J.; Si, X-Jie.; Zhu, J., 2005: Study on ultrasound-assisted decolorization of methyl orange with Fenton reagent. Employed with ultrasound, Fenton reagent, ultrasound-Fenton methods, performance and mechanism of decolorization and COD removal were investigated for methyl orange. Results indicated that little decolorization phenomenon was observed with ultraso...

Tarui, S.; Kuroda, K.; Nakayama, H., 1969: Pyruvic acid and lactic acid: interpretation of the test results. Nihon Rinsho. Japanese Journal of Clinical Medicine: Suppl:779-85

Nazarenko, V.I., 1983: Scientific and technical information in the service of agriculture. The USSR has a well structured documentation and information service for agriculture. The collection and processing of data and literature is divided among a large number of specialized institutes which keep in touch with each other and exchange i...

Tokranov, A.M., 1993: Length-age structure of the starry flounder, Platichthys stellatus, in the River Bolshaya esthuary sic West Kamchatka. Based on material collected in May-October 1990 the paper presents tabulated data on the size-age structure of the starry flounder (Platychthys stellatus) occurring in the estuary and lower reaches of the Bol'sya R. and in the adjacent shallo...