Role of MRP2 and MRP4 in renal organic anion excretion

性状（由申请方提供）：具有生理学、药理学和毒理学重要性的多种阴离子有机化合物的肾排泄主要通过肾近端小管（RPT）的主动分泌完成。通过RPT的OA分泌是通过跨基底外侧膜的摄取和跨顶膜的流出来完成的，并且许多转运蛋白已经涉及介导这两个步骤。基底外侧摄取步骤的细胞和分子生理学已明确定义，涉及转运蛋白OAT 1和OATS的活性。相比之下，几乎没有什么是已知的分子和细胞生理学的顶端流出步骤。本提案中概述的三个具体目标利用了在模型细胞系统中分离的克隆蛋白，并且被设计用于测试MRP 2和MRP 4（两者都定位于RPT细胞的顶膜）有助于主要由肾脏分泌的OA的分泌的假设（例如，β-内酰胺抗生素和抗病毒核苷衍生物）。重要的是，这些研究将提供管腔事件在药物相互作用和肾毒性发展中的潜在作用的观点，使其成为改善整体健康的重要工作。

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.