Tissue Distribution, Ontogeny, and Hormonal Regulation of Xenobiotic Transporters in Mouse Kidneys
Tissue Distribution, Ontogeny, and Hormonal Regulation of Xenobiotic Transporters in Mouse Kidneys
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DOI：
10.1124/dmd.109.027177
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发表时间：
2009-11-01
影响因子：
3.9
通讯作者：
Klaassen, Curtis D.
中科院分区：
文献类型：
--
作者：
Cheng, Xingguo;Klaassen, Curtis D.
肾脏在消除多种内源性和外源性化学物质方面起着重要作用。近年来，在哺乳动物肾脏中至少发现了37种异源转运蛋白。虽然已经取得了很大的进展，但关于肾脏中14种转运体(ATP结合盒[ABC]A1、心尖胆汁酸转运体[Asbt]、乳腺癌耐药蛋白、浓缩核苷转运体1、平衡核苷转运体[Ent]2、Ent3、磷酸钠共转运体[NPT]1、Npt2a、Npt2b、Npt2c、有机阴离子转运体[燕麦]5、有机阴离子转运体[Oatp]4c1、肽转运体2和尿酸转运体[Urat]1)的信息相当有限。因此，本研究的目的是研究这14种转运蛋白在小鼠肾脏中的组织分布、个体发育和激素调节。除肾脏外，Npt2b在小鼠的肝和肺中也有高表达，Npt2c在肝和结肠中有高表达，Asbt在回肠中有高表达，ABCA1在肝、肺、睾丸、卵巢和胎盘中也有高表达。其中大多数(14个转运体中的13个)在15天龄前的小鼠肾脏中低表达，这在一定程度上导致了胎儿和新生儿肾脏的排泄功能不成熟。一个例外是ent2，它在出生前高度表达，出生后逐渐下降，直到15日龄时达到成年水平。雄性为主(Urat1和Oatp4c1)和雌性为主(Oat5)的转运蛋白在小鼠肾脏中的性别差异表达分别是由于雄激素和雌激素的刺激作用。综上所述，异种转运蛋白在肾脏中的表达由组织、年龄和性激素决定。
Kidneys play important roles in the elimination of numerous endogenous and exogenous chemicals. In recent years, at least 37 xenobiotic transporters have been identified in mammalian kidneys. Although much progress has been made, information on 14 of these transporters (ATP-binding cassette [Abc] a1, apical sodium bile acid transporter [Asbt], breast cancer resistance protein, concentrative nucleoside transporter 1, equilibrative nucleoside transporter [Ent] 2, Ent3, sodium-phosphate cotransporter [Npt] 1, Npt2a, Npt2b, Npt2c, organic anion transporter [Oat] 5, organic anion-transporting polypeptide [Oatp] 4c1, peptide transporter 2, and uric acid transporter [Urat] 1) in kidneys is quite limited. Therefore, the purpose of the present study was to examine the tissue distribution, ontogeny, and hormonal regulation of these 14 transporters in kidneys of mice. Other than in kidneys, Npt2b is also highly expressed in liver and lung, Npt2c in liver and colon, Asbt in ileum, and Abca1 in liver, lung, testis, ovary, and placenta of mice. Most of these (13 of 14) transporters are lowly expressed in mouse kidneys until 15 days of age, which in part contributes to the immaturity of excretory function in fetal and newborn kidneys. One exception is Ent2, which is highly expressed before birth and gradually decreases after birth until reaching adult levels at 15 days of age. Gender-divergent expression of male-predominant (Urat1 and Oatp4c1) and female-predominant (Oat5) transporters in mouse kidneys is primarily due to stimulatory effects of androgens and estrogens, respectively. In conclusion, the mRNA expression of xenobiotic transporters in kidneys is determined by tissue, age, and sex hormones.