Effects of Metabolic Acidosis on Expression Levels of Renal Drug Transporters
Effects of Metabolic Acidosis on Expression Levels of Renal Drug Transporters
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DOI：
10.1007/s11095-010-0348-7
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发表时间：
2011-05-01
影响因子：
3.7
通讯作者：
Inui, Ken-ichi
中科院分区：
文献类型：
--
作者：
Gaowa, Arong;Motohashi, Hideyuki;Inui, Ken-ichi
在肾近曲小管细胞中，多种转运体在药物的分泌和重吸收过程中发挥重要作用。当诱发代谢性酸中毒时，肾脏会发生许多适应性变化。为探讨酸中毒时药物转运蛋白的变化及其对尿药物排泄的影响，采用Wistar/ST大鼠，以1.5%NH_4Cl自来水灌胃48 h，造成酸中毒。评价PSP或二甲双胍的药代动力学。此外，通过Western Blotting检测药物转运蛋白的表达水平，PSP的肾清除率显著降低，而二甲双胍的肌酐清除率和肾清除率无变化。Western blot结果显示，有机阴离子转运蛋白（OAT）3的蛋白表达水平降低。与OAT 3水平相反，OAT 1和有机阳离子转运蛋白（OCT）2水平未受影响。免疫组化结果显示，正常和酸中毒大鼠近端小管OAT 3蛋白均定位于基底外侧膜，代谢性酸中毒时肾排泄阴离子药物减少可能与OAT 3蛋白水平降低有关。
In the renal proximal tubular cells, various transporters play important roles in the secretion and reabsorption of drugs. When metabolic acidosis is induced, a number of adaptive changes occur in the kidney. The purpose of this study was to clarify the changes of drug transporters under the acidosis and the effects of these changes on urinary drug excretion.Wistar/ST rats were given 1.5% NH4Cl in tap water for 48 h to induce the acidosis. Pharmacokinetics of PSP or metformin was evaluated. In addition, expression levels of drug transporters were examined by Western Blotting.The renal clearance of PSP was markedly decreased, whereas the creatinine clearance and renal clearance of metformin were unchanged. Furthermore, Western blots indicated that the protein expression level of organic anion transporter (OAT) 3 was decreased. In contrast to OAT3 levels, OAT1 and organic cation transporter (OCT) 2 levels were unaffected. An immunohistochemical analysis showed that the OAT3 protein in the proximal tubules was localized in the basolateral membrane both of the normal and the acidosis rats.The decrease of renal excretion of anionic drugs during metabolic acidosis might be partly due to a reduction in the level of OAT3 protein.