Induction of glia maturation factor-β in proximal tubular cells leads to vulnerability to oxidative injury through the p38 pathway and changes in antioxidant enzyme activities
Induction of glia maturation factor-β in proximal tubular cells leads to vulnerability to oxidative injury through the p38 pathway and changes in antioxidant enzyme activities
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DOI：
10.1074/jbc.m301552200
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发表时间：
2003-08-29
影响因子：
4.8
通讯作者：
Imai, E
中科院分区：
文献类型：
--
作者：
Kaimori, J;Takenaka, M;Imai, E
蛋白尿是肾脏疾病进展的独立危险因素。胶质细胞成熟因子-β（GMF-β）是一种17-kDa的脑特异性蛋白质，最初作为神经营养因子从脑中纯化，通过蛋白尿在肾近端小管（PT）细胞中诱导。为了检测GMF-β在PT细胞中的作用，我们构建了连续表达GMF-β的PT细胞系。过表达GMF-β的PT细胞在用肿瘤坏死因子-α和血管紧张素II刺激后获得对细胞死亡的易感性，据报道这两者都引起氧化应激。GMF-β过表达还促进H2 O2的氧化损伤，导致非脑细胞（不仅PT细胞，而且NIH 3 T3细胞）中F-肌动蛋白的重组以及凋亡。在GMF-β-过表达细胞中的细胞内活性氧的测量显示，响应于肿瘤坏死因子-α、血管紧张素II和H2 O2刺激，H2 O2持续增加。H2 O2的持续增加是由H2 O2产生酶铜/锌-超氧化物歧化酶的活性增加，H2 O2还原酶过氧化氢酶和谷胱甘肽过氧化物酶的活性减少，以及细胞谷胱甘肽过氧化物酶底物GSH的含量减少引起的。p38信号通路在细胞持续氧化应激中起重要作用。总之，抗氧化酶活性的改变，特别是过氧化物清除缺陷，是GMF-β过表达细胞对细胞死亡易感性的基础。总之，我们认为，蛋白尿诱导肾PT细胞中的GMF-β可能通过增强氧化损伤在肾脏疾病的进展中发挥关键作用。
Proteinuria is an independent risk factor for progression of renal diseases. Glia maturation factor-beta (GMF-beta), a 17-kDa brain-specific protein originally purified as a neurotrophic factor from brain, was induced in renal proximal tubular (PT) cells by proteinuria. To examine the role of GMF-beta in PT cells, we constructed PT cell lines continuously expressing GMF-beta. The PT cells overexpressing GMF-beta acquired susceptibility to cell death upon stimulation with tumor necrosis factor-alpha and angiotensin II, both of which are reported to cause oxidative stress. GMF-beta overexpression also promoted oxidative insults by H2O2, leading to the reorganization of F-actin as well as apoptosis in non-brain cells (not only PT cells, but also NIH 3T3 cells). The measurement of intracellular reactive oxygen species in the GMF-beta-overexpressing cells showed a sustained increase in H2O2 in response to tumor necrosis factor-alpha, angiotensin II, and H2O2 stimuli. The sustained increase in H2O2 was caused by an increase in the activity of the H2O2-producing enzyme copper/zinc-superoxide dismutase, a decrease in the activities of the H2O2-reducing enzymes catalase and glutathione peroxidase, and a depletion of the content of the cellular glutathione peroxidase substrate GSH. The p38 pathway was significantly involved in the sustained oxidative stress to the cells. Taken together, the alteration of the antioxidant enzyme activities, in particular the peroxide-scavenging deficit, underlies the susceptibility to cell death in GMF-beta-overexpressing cells. In conclusion, we suggest that the proteinuria induction of GMF-beta in renal PT cells may play a critical role in the progression of renal diseases by enhancing oxidative injuries.