Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat.
Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat.
复制标题
DOI：
10.1371/journal.pone.0016165
复制
发表时间：
2011-01-31
期刊：
影响因子：
3.7
通讯作者：
Tiribelli C
中科院分区：
文献类型：
--
作者：
Gazzin S;Berengeno AL;Strazielle N;Fazzari F;Raseni A;Ostrow JD;Wennberg R;Ghersi-Egea JF;Tiribelli C
未结合胆红素（UCB）在脑中的蓄积导致胆红素脑病。Pgp（ABCb 1）和Mrp 1（ABCc 1）分别在血脑屏障（BBB）和血脑脊液屏障（BCSFB）中高表达，可能参与UCB在脑内的蓄积。我们研究了在不同发育阶段（出生后2、9、17和60天），长时间暴露于高浓度UCB对纯合子黄疸（jj）古恩大鼠与杂合子非黄疸（Jj）同窝仔大鼠两种转运蛋白表达的影响。在第9天，jj和Jj幼仔中BBB Pgp蛋白表达较低（约为成年值的16-27%），尽管jj动物中上调（在P9和P17-P60分别比年龄匹配的Jj动物高2倍和1.3倍）; Mrp 1蛋白表达几乎检测不到。相反，在BCSFB，P2时jj和Jj的Mrp 1蛋白表达相当高（成人值的60-70%），但从P9开始，jj幼崽的Mrp 1蛋白表达显著下调（50%），特别是在第四脑室脉络丛：Pgp几乎检测不到。Mrp 1蛋白下调伴随着适度的mRNA上调，这表明翻译而不是转录抑制。在体外暴露的脉络丛上皮细胞从正常大鼠UCB，也导致了Mrp 1蛋白的下调。这些数据表明，下调Mrp 1蛋白在BSCFB，导致UCB对上皮细胞的直接影响，可能会影响Mrp 1介导的血-脑脊液屏障的神经保护功能，实际上加强UCB的神经毒性。
Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced (jj) Gunn rats compared to heterozygous, not jaundiced (Jj) littermates at different developmental stages (2, 9, 17 and 60 days after birth). BBB Pgp protein expression was low in both jj and Jj pups at 9 days (about 16–27% of adult values), despite the up-regulation in jj animals (2 and 1.3 fold higher than age matched Jj animals at P9 and P17–P60, respectively); Mrp1 protein expression was barely detectable. Conversely, at the BCSFB Mrp1 protein expression was rather high (60–70% of the adult values) in both jj and Jj at P2, but was markedly (50%) down-regulated in jj pups starting at P9, particularly in the 4th ventricle choroid plexuses: Pgp was almost undetectable. The Mrp1 protein down regulation was accompanied by a modest up-regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity.
登录
查看更多内容
影响因子：
4.1
作者：
JOHNSON, JA;HAYWARD, JJ;SIEGEL, FL
通讯作者：
SIEGEL, FL
影响因子：
3.6
作者：
Jones, BR;Li, W;Vore, M
通讯作者：
Vore, M
影响因子：
4.7
作者：
Felix, RA;Barrand, MA
通讯作者：
Barrand, MA
影响因子：
4.1
作者：
Corich, Lucia;Aranda, Alejandro;Tiribelli, Claudio
通讯作者：
Tiribelli, Claudio
影响因子：
1.4
作者：
Daood M;Tsai C;Ahdab-Barmada M;Watchko JF
通讯作者：
Watchko JF