Urokinase induces survival or pro-apoptotic signals in human mesangial cells depending on the apoptotic stimulus.
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-X(L)-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.
Tkachuk
Natalia
N
Hannover Medical School, Carl-Neuberg Strasse 1, Hannover D-30625, Germany. tkatchouk.natalia@mh-hannover.de
Kiyan
Julia
J
Tkachuk
Sergey
S
Kiyan
Roman
R
Shushakova
Nelli
N
Haller
Hermann
H
Dumler
Inna
I
D017209:Apoptosis / Q000187:drug effects*; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D008360:Mannosephosphates / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009685:Nuclear Envelope / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494819:BAD protein, human; D008360:Mannosephosphates; D009842:Oligopeptides; D055293:Receptors, Urokinase Plasminogen Activator; D051025:bcl-Associated Death Protein; C027693:mannose-6-phosphate; C047981:arginyl-glycyl-aspartic acid; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D014568:Urokinase-Type Plasminogen Activator; D005947:Glucose