Deregulated apoptosis of MCs (mesangial cells) is associated with a number of kidney diseases including end-stage diabetic nephropathy. Cell death by apoptosis is a tightly orchestrated event, whose mechanisms are not completely defined. In the present study we show that the uPA (urokinase-type plasminogen activator)/uPAR (uPA receptor) system can initiate both cell survival and pro-apoptotic signals in human MCs in response to different apoptotic stimuli. uPA abrogated MC apoptosis induced by serum withdrawal conditions and enhanced apoptosis initiated in MCs by high glucose. Effects of uPA were independent of its proteolytic activity and required uPAR for both pro- and anti-apoptotic effects. Studies on the uPAR interactome provide evidence that the opposing effects of uPA were directed via different uPAR-interacting transmembrane partners. Exposure of MCs to RGD (Arg-Gly-Asp) peptide led to abrogation of the anti-apoptotic effect of uPA, which implies involvement of integrins in this process. A pro-apoptotic effect of uPA under high-glucose conditions was mediated via association of uPAR and the cation-independent M6P (mannose-6-phosphate)/IGF2R (insulin-like growth factor 2 receptor). Both receptors were co-precipitated and co-localized in MCs. Studies on the underlying signalling indicate that the ERK1/2 (extracellular-signal-regulated kinase 1/2), Akt and BAD (Bcl-2/Bcl-XL-antagonist, causing cell death) protein were involved in regulation of apoptosis by uPA in MCs. M6P/IGF2R mediated BAD perinuclear localization during apoptosis initiated by uPA and high glucose. In conclusion, we provide evidence that, in MCs, the uPA/uPAR system regulates survival/apoptosis processes in a stimulus-specific fashion via a mitochondria-dependent mechanism and that BAD protein serves as a downstream molecule.
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October 2008
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Research Article|
September 25 2008
Urokinase induces survival or pro-apoptotic signals in human mesangial cells depending on the apoptotic stimulus
Natalia Tkachuk;
Natalia Tkachuk
1
*Hannover Medical School, Carl-Neuberg Straße 1, Hannover D-30625, Germany
1To whom correspondence should be addressed (email tkatchouk.natalia@mh-hannover.de).
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Julia Kiyan;
Julia Kiyan
*Hannover Medical School, Carl-Neuberg Straße 1, Hannover D-30625, Germany
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Sergey Tkachuk;
Sergey Tkachuk
*Hannover Medical School, Carl-Neuberg Straße 1, Hannover D-30625, Germany
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Roman Kiyan;
Roman Kiyan
†Hannover Lazer Center, Hollerithallee 8, Hannover D-30419, Germany
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Nelli Shushakova;
Nelli Shushakova
*Hannover Medical School, Carl-Neuberg Straße 1, Hannover D-30625, Germany
‡Phenos GmbH, Feodor-Lynen Strasse 5, Hannover D-30625, Germany
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Hermann Haller;
Hermann Haller
*Hannover Medical School, Carl-Neuberg Straße 1, Hannover D-30625, Germany
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Inna Dumler
Inna Dumler
*Hannover Medical School, Carl-Neuberg Straße 1, Hannover D-30625, Germany
§Experimental and Clinical Research Center-ECRC, at the Max Delbrück Center for Molecular Medicine, Wiltbergstraße 50, Berlin D-13125, Germany
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Publisher: Portland Press Ltd
Received:
December 10 2007
Revision Received:
June 03 2008
Accepted:
June 19 2008
Accepted Manuscript online:
June 19 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 415 (2): 265–273.
Article history
Received:
December 10 2007
Revision Received:
June 03 2008
Accepted:
June 19 2008
Accepted Manuscript online:
June 19 2008
Citation
Natalia Tkachuk, Julia Kiyan, Sergey Tkachuk, Roman Kiyan, Nelli Shushakova, Hermann Haller, Inna Dumler; Urokinase induces survival or pro-apoptotic signals in human mesangial cells depending on the apoptotic stimulus. Biochem J 15 October 2008; 415 (2): 265–273. doi: https://doi.org/10.1042/BJ20071652
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