Urokinase induces survival or pro-apoptotic signal in human mesangial cells depending on the apoptotic stimulus
Résumé
Deregulated apoptosis of mesangial cells (MCs) 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. We show that the urokinase (uPA)/urokinase receptor (uPAR) system can initiate both cell survival and pro-apoptotic signals in human MCs in response to different apoptotic stimuli. uPA abrogated MCs 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 of uPA. Studies on uPAR interactome provide evidence that the opposing effects of uPA were directed via different uPAR-interacting transmembrane partners. Exposure of MCs to RGD peptide led to abrogation of anti-apoptotic effect of uPA that 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 mannose-6-phosphate (M6P)/insulin growth factor 2 receptor (IGF2R). Both receptors were coprecipitated and colocalized in MCs. Studies on the underlying signaling indicate that the ERK1/2, AKT and BAD 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 mitochondria-dependent mechanism and that BAD protein serves as a downstream molecule.
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