Molecular Organization or Renal Organic Anion Transport

分子组织或肾脏有机阴离子转运

• 批准号: 7569334
• 负责人: STEPHEN H WRIGHT
• 金额: $ 26.51万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7569334
• 关键词: Animal Model; Animals; Anions; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Apical; Biological; Biological Models; Carrier Proteins; Cell Culture System; Cell model; Cell physiology; Cells; Characteristics; Chelating Agents; Cultured Cells; Data; Development; Drug Interactions; Epithelial; Event; Excretory function; Failure; Family; Family suidae; Genetic Models; Goals; Heavy Metals; Human Cloning; Kidney; Length; Liver; MDCK cell; Measurement; Mediating; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Profiling; Monobactams; Moon; Morphology; Multidrug Resistance-Associated Proteins; Mus; Nephrotoxic; Nucleosides; Organic Anion Transport Protein 1; Organic Anion Transporters; Orsan; Oryctolagus cuniculus; Pharmaceutical Preparations; Phase; Physiological; Plasma; Play; Process; Proteins; Proximal Kidney Tubules; Rattus; Relative (related person); Renal clearance function; Renal tubule structure; Research; Research Design; Research Personnel; Role; Side; Subgroup; System; Techniques; Testing; Time; Tissues; Wild Type Mouse; Work; base; design; immunocytochemistry; inhibitor/antagonist; innovation; interest; luminal membrane; mouse model; nephrotoxicity; programs; research study; response

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.

肾脏是体内大量阴离子化合物排泄的主要途径。 生理、药理和毒理学意义(包括对内酰胺类抗生素；核苷- 衍生的抗病毒化合物；非类固醇抗炎药(NSAIDs)；阴离子螯合剂和 重金属的络合物)。此外，肾与肝共同起着重要的辅助作用。 血浆中其他许多阴离子代谢物的水平为II期代谢。这些有机物在肾脏中的排泄 阴离子(OAS)主要由肾近端细胞介导的跨上皮细胞分泌过程控制 小管(RPT)。近年来，越来越多的证据支持了OAS的肾脏分泌物涉及 许多单独的转运蛋白在基底外侧(小管周围)和 Rpt的根尖(腔)膜。尽管现在已经很好地理解了基侧“进入步骤”， 就我们对月球的理解而言，RPT的管膜代表了月球的黑暗面 肾脏OA分泌物。尽管事实表明至少有8个不同的转运蛋白在 RPT的管腔膜对于这些潜在的“候选”管腔转运体来说都不是它们的范围 了解对肾脏卵泡刺激素分泌的影响。这里提出的实验代表了一个综合计划 旨在确定一组腔转运体对肾脏OA分泌的贡献的研究，即， 多药耐药相关蛋白(MRPs)。我们结合使用克隆的运输蛋白和 通过使用完整的肾小管和完整的动物的研究，建立培养细胞系统的模型。我们将发展 培养细胞表达克隆转运蛋白的模型系统评估相对贡献 两种不同的有机阴离子转运体(燕麦，即OAT1和OAT3)的分泌 和两个不同的管腔转运蛋白(即MRP2和MRP4)。这些模型单元格将提供所需的数据 用分离的单个肾近端小管和全肾清除率设计和解释实验 使用野生型小鼠和缺乏选定的OA转运蛋白的遗传模型的测量。这个 这一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；以及整体 ORSAN/ORANISSIC，并将首次形成对Lumina和Oreanisic的潜在作用的看法 DRUE-DRUA相互作用中的基底外侧事件与肾毒性的发展。