Molecular Organization or Renal Organic Anion Transport

肾脏是从体内排泄大量阴离子化合物的主要途径， 生理学、药理学和毒理学意义（包括β-内酰胺类抗生素;核苷- 衍生的抗病毒化合物;非甾体抗炎药（NSAID）;和阴离子螯合剂， 重金属的螯合物）。此外，肾与肝一起在控制 II期代谢的许多其他阴离子代谢物的血浆水平。肾脏排泄这些有机物 阴离子（OAs）主要由肾近端细胞介导的跨上皮分泌过程控制。 肾小管（RPT）。近年来，越来越多的证据支持这一论点，即肾分泌的OAs涉及 许多单独的转运蛋白在基底外侧（管周）表达的协同活性， RPT的顶（腔）膜。虽然基底外侧的“进入步骤”现在已经相当清楚， RPT的管腔膜代表了“月球的黑暗面”，就我们对月球的理解而言， 肾OA分泌。尽管事实上至少有8种不同的转运蛋白已被证明是表达在 对于这些潜在的“候选”管腔转运蛋白中的任何一种，RPT的管腔膜都不是它们的 了解对肾OA分泌影响。这里提出的实验代表了一个综合方案 旨在确定一组管腔转运蛋白对肾OA分泌的贡献的研究，即， 多药耐药相关蛋白（MRPs）。我们将克隆转运蛋白的使用与联合收割机结合起来， 使用完整的肾小管和完整的动物进行研究，建立培养细胞系统模型。我们将开发 模型系统培养表达克隆转运蛋白的细胞， 分泌两种不同的基底外侧“有机阴离子转运蛋白”转运蛋白（OAT;即，OAT 1和OAT 3） 和两种不同的管腔转运蛋白（即，MRP 2和MRP 4）。这些模型单元将提供所需的数据， 设计并解释使用单个离体肾近端小管和全肾清除率的实验 使用野生型小鼠和缺乏所选OA转运蛋白的遗传模型进行测量。的 这项研究计划的创新设计允许在三个月内评估分泌的机制基础。 生物组织的不同层次：分子和细胞;上皮/组织;和整体 奥尔桑/oreaneland，并将首次开发一个视图的潜在作用，这两个管腔和 药物-药物相互作用中的基底侧事件和肾毒性的发展。

The kidney is the principal means for excretion from the body of a vast array of anionic compounds of physiological, pharmacological and toxicological significance (including p-lactam antibiotics; nucleoside- derived antiviral compounds; non-steroidal anti-inflammatory drugs (NSAIDs); and anionic chelators and chelates of heavy metals). In addition, the kidney plays a critical auxiliary role with the liver in controlling plasma levels of many other anionic metabolites of Phase II metabolism. Renal excretion of these organic anions (OAs) is dominated by the processes of transepithelial secretion mediated by cells of the renal proximal tubule (RPT). In recent years, increasing evidence supports the contention that renal secretion of OAs involves the concerted activity of many separate transport proteins that are expressed in the basolateral (peritubular) and apical (luminal) membranes of RPTs. Although the basolateral 'entry step' is now reasonably well understood, the luminal membrane of the RPT represents 'the dark side of the moon' with respect to our understanding of renal OA secretion. Despite the fact that at least 8 distinct transporters have been shown to be expressed in the luminal membrane of RPT for none of these potential 'candidate' luminal transporters is the extent of their influence on renal OAsecretion understood. The experiments proposed here represent an integrated program of study designed to establish the contribution to renal OA secretion of one group of luminal transporters, i.e., the multidrug resistance-associate proteins (the MRPs). We combine the use of cloned transport proteins and model cultured cell systems with studies that employ intact renal tubules and intact animals. We will develop model systems that cultured cells expressing cloned transport proteins to assess the relative contribution to secretion of two distinct basolateral 'organic anion transporters' transporters (OATs; i.e., OAT1 and OAT3) and two distinct luminal transporters (i.e., MRP2 and MRP4). These model cells will provide data required to design and interpret experiments using isolated single renal proximal tubules and whole renal clearance measurements that employ both wild type mice and genetic models that lack selected OA transporters. The innovative design of this research program permits assessment of the mechanistic basis of secretion at three distinct levels of biological organization: the molecular and cellular; the epithelial/tissue; and the whole orsan/oreanismic, and will develop for the first time a view of the potential role of both luminal and basolateral events in drue-drua interactions and the development of nephrotoxicity.