Urokinase induces survival or pro-apoptotic signals in human mesangial cells depending on the apoptotic stimulus
Urokinase induces survival or pro-apoptotic signals in human mesangial cells depending on the apoptotic stimulus
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DOI：
10.1042/bj20071652
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发表时间：
2008-10-15
影响因子：
4.1
通讯作者：
Dumler, Inna
中科院分区：
文献类型：
--
作者：
Tkachuk, Natalia;Kiyan, Julia;Dumler, Inna
肾小球系膜细胞(MCs)的非调控凋亡与包括终末期糖尿病肾病在内的多种肾脏疾病有关。细胞凋亡是一个紧密协调的事件，其机制尚不完全清楚。在本研究中，我们发现uPA(尿激酶型纤溶酶原激活物)/uPAR(uPA受体)系统可以在不同的凋亡刺激下启动人MC的细胞存活和促凋亡信号。UPA可抑制血清撤除条件诱导的MC凋亡，增强高糖诱导的MC凋亡。UPA的作用与其蛋白水解性无关，并需要uPAR来发挥促和抗细胞凋亡的作用。对uPAR相互作用组的研究提供了证据，证明uPA的相反作用是通过不同的uPAR相互作用的跨膜伙伴来实现的。RGD(Arg-Gly-Asp)多肽可抑制uPA的抗凋亡作用，提示整合素参与了这一过程。UPA在高糖条件下的促凋亡作用是通过uPAR和非依赖于阳离子的M6P(甘露糖-6-磷酸)/IGF2R(胰岛素样生长因子2受体)介导的。两种受体在MCs中共沉淀和共定位。对潜在信号的研究表明，ERK1/2(细胞外信号调节蛋白1/2)、Akt和Bad(Bcl2/BclX-L拮抗剂，导致细胞死亡)蛋白参与了uPA对MCs凋亡的调控。M6P/IGF2R介导uPA和高糖诱导的细胞凋亡过程中核周定位不良。总之，我们提供的证据表明，在MC中，uPA/uPAR系统通过线粒体依赖的机制以刺激特异性的方式调节生存/凋亡过程，BAD蛋白作为下游分子发挥作用。
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 under-lying 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.