Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis
Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis
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DOI：
10.1152/ajprenal.00139.2008
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发表时间：
2008-07-01
影响因子：
4.2
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Chen, Jiarong;Terada, Tomohiro;Inui, Ken-ichi
胆汁淤积期间，胆汁酸主要排泄到尿液中，但肾脏对胆汁淤积的适应性反应，特别是肾脏分泌胆汁酸的分子机制尚未得到充分了解。有机阴离子转运蛋白（OAT1 和 OAT3）负责阴离子化合物在肾基底外侧膜的膜转运。在本研究中，我们研究了 OAT1 和 OAT3 在肾脏处理胆汁酸方面的病理生理学作用。与 Sprague-Dawley (SD) 大鼠（野生型）相比，卫材高胆红素血症大鼠 (EHBR) 是一种没有多药耐药相关蛋白 2 的突变大鼠，其血清和尿胆汁酸浓度较高。与SD大鼠相比，EHBR中大鼠OAT3的蛋白表达水平显着增加，而大鼠OAT1的表达水平没有变化。大鼠和人OAT3（而非OAT1）的转运活性受到各种胆汁酸（例如鹅去氧胆酸和胆酸）的显着抑制。胆酸、甘氨胆酸和牛磺胆酸主要在胆汁淤积期间增加，由OAT3转运。尽管 OAT3 蛋白上调，但 EHBR 中β-内酰胺抗生素头孢替安（OAT3 的特异性底物）的血浆浓度比 SD 大鼠增加更多。这可能是由于胆汁酸通过 OAT3 竞争性抑制头孢替安转运。总之，本研究清楚地表明，OAT3 负责胆汁淤积期间肾脏分泌胆汁酸，并且 OAT3 底物的药代动力学特征可能受到胆汁淤积的影响。
During cholestasis, bile acids are mainly excreted into the urine, but adaptive renal responses to cholestasis, especially molecular mechanisms for renal secretion of bile acids, have not been well understood. Organic anion transporters (OAT1 and OAT3) are responsible for membrane transport of anionic compounds at the renal basolateral membranes. In the present study, we investigated the pathophysiological roles of OAT1 and OAT3 in terms of renal handling of bile acids. The Eisai hyperbilirubinemic rats (EHBR), mutant rats without multidrug resistance-associated protein 2, showed higher serum and urinary concentrations of bile acids, compared with Sprague-Dawley (SD) rats (wild type). The protein expression level of rat OAT3 was significantly increased in EHBR compared with SD rats, whereas the expression of rat OAT1 was unchanged. The transport activities of rat and human OAT3, but not OAT1, were markedly inhibited by various bile acids such as chenodeoxycholic acid and cholic acid. Cholic acid, glycocholic acid, and taurocholic acid, which mainly increased during cholestasis, are transported by OAT3. The plasma concentration of beta-lactam antibiotic cefotiam, a specific substrate for OAT3, was more increased in EHBR than in SD rats despite upregulation of OAT3 protein. This may be due to the competitive inhibition of cefotiam transport by bile acids via OAT3. In conclusion, the present study clearly demonstrated that OAT3 is responsible for renal secretion of bile acids during cholestasis and that the pharmacokinetic profile of OAT3 substrates may be affected by cholestasis.