Gender differences in mRNA expression of ATP-binding cassette efflux and bile acid transporters in kidney, liver, and intestine of 5/6 nephrectomized rats
Gender differences in mRNA expression of ATP-binding cassette efflux and bile acid transporters in kidney, liver, and intestine of 5/6 nephrectomized rats
复制标题
DOI：
10.1124/dmd.107.014845
复制
发表时间：
2008-01-01
影响因子：
3.9
通讯作者：
Klaassen, Curtis
中科院分区：
文献类型：
--
作者：
Lu, Hong;Klaassen, Curtis
多药耐药蛋白（multidrug resistance proteins，Mdr）、多药耐药相关蛋白（multidrug resistance-associated proteins，Mrp）和乳腺癌耐药蛋白（breast cancer resistance protein，Bcrp/Abcg 2）等ATP结合盒（ATP binding cassette，ABC）转运蛋白在组织防御中发挥重要作用。Abcg 5/g8在胆固醇流出中是必需的。本研究的目的是阐明这些转运蛋白和胆汁酸转运蛋白在慢性肾脏疾病（CKD）中的表达变化及其分子机制。在5/6肾切除术（Nx）后7周，用分支DNA信号放大分析定量雄性和雌性Nx大鼠的肾、肝、空肠和大肠中的16种上述转运蛋白的mRNA表达。在Nx雄性动物中，所有转运蛋白的肠道表达保持不变;除Mdr 1a、Mrp 3和Abcg 8增加外，大多数转运蛋白的肝脏表达未发生变化。在男性残肾中，肾优势转运蛋白Abcg 2降低并与CKD严重程度相关，而Mdr 1b、Mrp 3和回肠胆汁酸转运蛋白升高并与CKD严重程度相关。Nx雌性动物中基本不存在此类变化。这些转运蛋白的肾脏改变与细胞因子的增加和/或核受体如雌激素受体α和糖皮质激素受体的减少相关。肾蛋白表达的Mrp 2增加，而Mrp 4保持不变，在两种性别的Nx大鼠。用白细胞介素（IL）-1 β和IL-6处理大鼠近曲小管NRK-52 E细胞可增加Mrp 3 mRNA的表达。总之，在CKD期间，许多ABC转运蛋白的肾脏表达在转录水平上发生改变，而大多数ABC转运蛋白的肝脏mRNA表达保持不变。CKD时肾脏类固醇激素受体表达下调和炎性细胞因子表达增加可能与肾脏转运蛋白基因表达改变有关。
ATP-binding cassette (ABC) transporters including multidrug resistance proteins (Mdr), multidrug resistance-associated proteins (Mrp), and breast cancer resistance protein (Bcrp/Abcg2) play major roles in tissue defense. Abcg5/g8 is essential in cholesterol efflux. The present study was aimed at elucidating alteration in expression of these transporters and bile-acid transporters during chronic kidney disease (CKD) and underlying molecular mechanisms. Seven weeks after 5/6 nephrectomy (Nx), mRNA expression of 16 aforementioned transporters in kidney, liver, jejunum, and large intestine of male and female Nx rats was quantified with the branched DNA signal amplification assay. In Nx males, intestinal expression of all the transporters remained unchanged; hepatic expression of most transporters was not altered, except increases in Mdr1a, Mrp3, and Abcg8. In male remnant kidneys, kidney-predominant transporter Abcg2 decreased and correlated with CKD severity, whereas Mdr1b, Mrp3, and ileal bile-acid transporter increased and correlated with CKD severity. Such changes were largely absent in Nx females. Renal alterations of these transporters correlated with increases of cytokines and/or decreases of nuclear receptors such as estrogen receptor alpha and glucocorticoid receptor. Renal protein expression of Mrp2 increased, whereas that of Mrp4 remained unchanged in both genders of Nx rats. Treatment of rat proximal tubule NRK-52E cells with interleukin (IL)-1 beta and IL-6 increased Mrp3 mRNA expression. In conclusion, during CKD, renal expression of many ABC transporters was altered at the transcriptional level, whereas hepatic mRNA expression of most ABC transporters remained unchanged. Down-regulation of steroid hormone receptors and increase of inflammatory cytokines may contribute to alteration of transporter gene expression in kidney during CKD.