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Gunn 大鼠血脑屏障和血脑脊液屏障中胆红素对 Mrp1（ABCC1）和 Pgp（ABCB1）的调节作用。

Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by bilirubin at the blood-CSF and blood-brain barriers in the Gunn rat.

机构信息

Centro Studi Fegato, Basovizza Trieste, Italy.

出版信息

PLoS One. 2011 Jan 31;6(1):e16165. doi: 10.1371/journal.pone.0016165.

DOI:10.1371/journal.pone.0016165
PMID:21297965
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3031532/
Abstract

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 4(th) 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.

摘要

未结合胆红素 (UCB) 在脑内的蓄积会导致胆红素脑病。多药耐药蛋白 P 糖蛋白 (PGP)（ABCB1）和多药耐药相关蛋白 1 (MRP1)（ABCC1）分别在血脑屏障 (BBB) 和血脑脊液屏障 (BCSFB) 中高度表达，可能调节 UCB 在脑内的蓄积。我们研究了长时间暴露于高浓度 UCB 对同型黄疸（jj）Gunn 大鼠和异型非黄疸（Jj）同窝仔鼠在不同发育阶段（出生后 2、9、17 和 60 天）两种转运蛋白表达的影响。尽管 jj 动物存在上调（出生后 9 天和 17-60 天分别比年龄匹配的 Jj 动物高 2 倍和 1.3 倍），但 jj 和 Jj 仔鼠在 9 天时 BBB Pgp 蛋白表达均较低（约为成人值的 16-27%）；MRP1 蛋白表达几乎检测不到。相反，在 BCSFB，jj 和 Jj 仔鼠在出生后第 2 天 MRP1 蛋白表达水平相当高（成人值的 60-70%），但从第 9 天开始，jj 仔鼠明显（50%）下调，特别是在第四脑室脉络丛：Pgp 几乎检测不到。MRP1 蛋白下调伴随着 mRNA 的适度上调，提示存在翻译而非转录抑制。体外将正常大鼠脉络丛上皮细胞暴露于 UCB 也导致 MRP1 蛋白下调。这些数据表明，UCB 对上皮细胞的直接作用导致 BCSFB 中 MRP1 蛋白下调，可能影响血脑脊液屏障的 MRP1 介导的神经保护功能，并实际上增强 UCB 的神经毒性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/975d/3031532/c09f60bf47e0/pone.0016165.g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/975d/3031532/14d51b0b4e07/pone.0016165.g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/975d/3031532/106cb755f40f/pone.0016165.g001.jpg
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