Role of MRP2 and MRP4 in renal organic anion excretion

描述（由申请人提供）：肾脏排泄多种具有生理、药理学和毒理学重要性的阴离子有机化合物主要是通过肾近端小管（RPT）的活跃分泌来完成的。RPT的OA分泌是通过基底外膜的摄取和顶膜的外排来完成的，许多转运蛋白参与了这两个步骤的介导。基底外侧摄取步骤的细胞和分子生理学是明确的，涉及转运蛋白OAT1和OATS的活动。相比之下，实际上对顶端外排步骤的分子和细胞生理学一无所知。本提案中概述的三个具体目标利用了从模型细胞系统中分离的克隆蛋白，旨在验证MRP2和MRP4的假设，这两个蛋白都位于RPT细胞的顶膜上，有助于主要由肾脏排泄的OAs的分泌（例如，b -内酰胺抗生素和抗病毒核苷衍生物）。重要的是，这些研究将提供在药物-药物相互作用和肾毒性发展中的腔内事件的潜在作用的观点，使其对改善整体健康具有重要意义。

DESCRIPTION (provided by applicant): Renal excretion of a wide variety of anionic organic compounds of physiological, pharmacological, and toxicological importance is accomplished primarily through active secretion by the renal proximal tubule (RPT). OA secretion by the RPT is accomplished by uptake across the basolateral membrane and efflux across the apical membrane, and many transporters have been implicated in mediating both steps. The cellular and molecular physiology of the basolateral uptake step is well defined, involving the activities of the transporters OAT1 and OATS. In contrast, virtually nothing is known about the molecular and cellular physiology of the apical efflux step. The three specific aims outlined in this proposal make use of cloned proteins isolated in model cell systems, and are designed to test the hypothesis that MRP2 and MRP4, both of which are localized to the apical membrane of RPT cells, contribute to the secretion of OAs primarily excreted by the kidney (e.g., B-lactam antibiotics and antiviral nucleoside derivatives). Importantly, these studies will provide a view of the potential role of luminal events in drug-drug interactions and the development of nephrotoxicity, making it important work for improving overall health.