Modulation of organic anion transporting polypeptide 1 and multidrug resistance protein 3 expression in the liver and kidney of Gunn rats
Modulation of organic anion transporting polypeptide 1 and multidrug resistance protein 3 expression in the liver and kidney of Gunn rats
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DOI：
10.1016/j.hepres.2004.02.008
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发表时间：
2004-05-01
影响因子：
4.2
通讯作者：
Adachi, Y
中科院分区：
文献类型：
--
作者：
Higuchi, K;Kobayashi, Y;Adachi, Y
背景：Gunn 大鼠是 I 型克里格勒-纳贾尔综合征 (CNS) 的动物模型，由于胆红素结合缺陷而出现黄疸。胆红素 UDP-葡萄糖醛酸基转移酶 (UGT1A1) 在胆红素葡萄糖醛酸化中起关键作用，据报道在 CNS 1 型中存在缺陷。另一方面，人们对 Gunn 大鼠中有机阴离子转运蛋白的表达知之甚少。在本研究中，我们评估了 Gunn 大鼠肝脏和肾脏中有机阴离子转运多肽 (oatp) I 和 2、多药耐药相关蛋白 (mrp) 2 和 mrp3 的表达。方法：取Gunn大鼠和正常SD大鼠（每组6只）的血清样本、肝肾组织。通过构建的逆转录聚合酶链式反应 (RT-PCR) 评估 oatp1、oatp2、mrp2 和 mrp3 mRNA 的半定量 mRNA 表达。通过蛋白质印迹和免疫组织化学测定蛋白质表达。结果：在 Gunn 大鼠中观察到血清非结合胆红素浓度显着升高（129.4 +/- 34.8 mumol/l）。 Gunn大鼠肝脏中oatp1和oatp2 mRNA的表达分别比SD大鼠低44%（P < 0.01）和35%（P < 0.01）。 Gunn大鼠肝脏oatp1蛋白表达比SD大鼠低37%（P < 0.05）。与oatp I相比，Gunn大鼠的肝脏mrp3 mRNA和蛋白表达分别比SD大鼠高76%（P < 0.01）和557%（P < 0.01）。 Gunn大鼠和SD大鼠的肝脏oatp2和mrp2蛋白表达没有显着差异。与蛋白质印迹分析一样，免疫组织化学染色显示 Gunn 大鼠肝脏中 oatp I 表达减少，mrp3 蛋白表达增加。 Gunn 大鼠肾脏中 oatp I 表达减少，mrp3 表达增加。结论：Gunn大鼠肝脏和肾脏中oatp1表达减少，mrp3表达增加。在 Gunn 大鼠中，与肝细胞中未结合胆红素的保留相关的 UGT1A1 活性缺陷可能会调节这些转运蛋白的表达。 (C) 2004 Elsevier B.V. 保留所有权利。
Background: Gunn rat is an animal model of Crigler-Najjar syndrome (CNS) type I that develops jaundice due to defect of bilirubin conjugation. Bilirubin UDP-glucuronosyltransferase (UGT1A1), which plays a critical role in bilirubin glucuronidation, has been reported to be deficient in CNS type 1. On the other hand, little is known about the expression of organic anion transporters in Gunn rats. In the present study, we evaluated expressions of organic anion transporting polypeptide (oatp) I and 2, multidrug resistance-associated protein (mrp) 2 and mrp3 in the liver and kidney of Gunn rats. Methods: Serum samples, liver and kidney tissues were obtained from Gunn rats and normal SD rats (n = 6, in each group). Semi-quantitative mRNA expression of oatp1, oatp2, mrp2, and mrp3 mRNA was evaluated by constructed reverse transcription-polymerase chain reaction (RT-PCR). Protein expressions were determined by Western blotting and by immunohistochemistry. Results: Marked elevation of serum unconjugated bilirubin concentration (129.4 +/- 34.8 mumol/l) was observed in Gunn rats. Hepatic expression of oatp1 and oatp2 mRNA was 44% (P < 0.01) and 35% (P < 0.01) lower in Gunn rats than in SD rats, respectively. Hepatic oatp1 protein expression was 37% (P < 0.05) lower in Gunn rats than in SD rats. In contrast to oatp I, hepatic expression of mrp3 mRNA and protein was 76% (P < 0.01) and 557% (P < 0.01) higher in Gunn rats than in SD rats, respectively. Hepatic expression of oatp2 and mrp2 protein was not significantly different between Gunn rats and SD rats. Like the Western blot analysis, immunohistochemical staining disclosed decrease of oatp I and increase of mrp3 protein expressions in the liver of Gunn rats. Decrease of oatp I and increase of mrp3 expressions were also observed in the kidney of Gunn rats. Conclusion: Decreased expression of oatp1 and increased expression of mrp3 were observed in the liver and kidney of Gunn rats. Deficient UGT1A1 activity-associated retention of unconjugated bilirubin in the hepatocytes may modulate the expressions of these transporters in Gunn rats. (C) 2004 Elsevier B.V. All rights reserved.