Induction of glucose-6-phosphate dehydrogenase by lipopolysaccharide contributes to preventing nitric oxide-mediated glutathione depletion in cultured rat astrocytes

被引:79
作者
García-Nogales, P [1 ]
Almeida, A [1 ]
Fernández, E [1 ]
Medina, JM [1 ]
Bolaños, JP [1 ]
机构
[1] Univ Salamanca, Dept Bioquim & Biol Mol, Edificio Dept, Salamanca 37007, Spain
关键词
glucose-6-phosphate dehydrogenase; pentose phosphate pathway; nitric oxide; glutathione; astrocyte; neurodegeneration;
D O I
10.1046/j.1471-4159.1999.721750.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Treatment of cultured rat astrocytes with lipopolysaccharide (LPS; 1 mu g/ml) increased mRNA expression of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting step in the pentose phosphate pathway (PPP), in a time-dependent fashion (0-24 h). This effect was accompanied by an increase in G6PD activity (1.74-fold) and in the rate of glucose oxidation through the PPP (6.32-ford). Inhibition of inducible nitric oxide synthase (iNOS) activity by 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT; 50 mu M) did not alter the LPS-mediated enhancement of G6PD mRNA expression or PPP activity. Blockade of nuclear factor kappa B (NF-kappa B) activation by N-benzyloxycarbonyl- IIe-Glu-(O-tert-butyl)-Ala-leucinal (1 mu M) prevented the expression of both iNOS mRNA and G6PD mRNA, suggesting that iNOS and G6PD are cc-induced by LPS through a common transcriptional pathway involving NF-kappa B activation. Incubation of cells with LPS for 24 h increased intracellular NADPH concentrations (1.63-fold) as compared with untreated cells, but GSH concentrations were not modified by LPS treatment up to 60 h of incubation. However. inhibition of G6PD activity by dehydroepiandrosterone (DHEA; 100 mu M), which prevented LPS-mediated enhancements in PPP activity and NADPH concentrations, caused a 50% decrease in the GSH/GSSG ratio after 24-36 h and in GSH concentrations after 60 h of incubation. Furthermore, the changes in glutathione concentrations caused by DHEA were abolished by AMT, suggesting that nitric oxide and/or its reactive derivatives would be involved in this process. From these results, we conclude that LPS-mediated G6PD expression prevents GSH depletion due to nitric oxide and suggest that this phenomenon may be a contributing factor in the defense mechanisms that protect astrocytes against nitric oxide-mediated cell injury.
引用
收藏
页码:1750 / 1758
页数:9
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