REGULATION OF RENAL XENOBIOTIC EXCRETION

肾脏异生物排泄的调节

• 批准号: 6162311
• 负责人: D S MILLER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162311
• 关键词: Osteichthyes; P glycoprotein; drug /agent; drug metabolism; excretion; fluorescence microscopy; hormone regulation /control mechanism; hormones; renal tubular transport; renal tubule; tissue /cell culture

Summary of Work: The vertebrate renal proximal tubule is responsible for the excretory transport of a large number of potentially toxic chemicals, including, waste products of normal metabolism, drugs, environmental pollutants and drug and pollutant metabolites. These chemicals are handled by multiple specific, secretory transport systems that remove them from the blood and concentrate them in urine. At present little is known about the control of these transport systems. We are using comparative models (intact renal proximal tubules from teleost fish and mammalian renal slices and cells in culture) in combination with fluorescence microscopy (conventional and confocal), video imaging, intracellular microinjection and isolated membrane vesicle techniques to define the cellular mechanisms that control xenobiotic transport. Initial confocal imaging experiments have shown that all the xenobiotic transport systems in killifish renal proximal tubules are under short- term control of protein kinase C (PKC). For example, transport mediated by the organic anion system and by the multidrug resistance (MDR) transporter (p-glycoprotein) fell when tubules were exposed to phorbol ester or to diacylglycerol and that transport through those systems increased when tubules were exposed to protein kinase inhibitors, which also blocked phorbol ester effects. The goals of this project are to identify the physiologically relevant extracellular signals (hormones, metabolites, xenobiotics) and the intracellular signalling pathways involved in the control of organic anion transport system and p- glycoprotein in renal proximal tubule.

工作总结：脊椎动物肾近端小管负责 大量潜在有毒化学物质的排泄运输， 包括正常代谢的废物、药物、环境 污染物以及药物和污染物代谢物。 这些化学物质 由多个特定的分泌运输系统处理， 从血液中分离出来并浓缩在尿液中。 目前， 了解这些运输系统的控制。 我们正在使用 比较模型（来自硬骨鱼的完整肾近端小管和 哺乳动物肾切片和培养物中的细胞）与 荧光显微镜（常规和共聚焦），视频成像， 细胞内显微注射和分离膜囊泡技术， 定义控制异生物质运输的细胞机制。 最初的共聚焦成像实验表明，所有的异生物质 鱼肾近端小管的运输系统处于短- 蛋白激酶C（PKC）的术语控制。 例如，转运介导 通过有机阴离子系统和通过多药耐药（MDR） 当肾小管暴露于佛波醇时， 酯或二酰基甘油以及通过这些系统转运 当肾小管暴露于蛋白激酶抑制剂时， 也阻断佛波醇酯的作用。 该项目的目标是 识别生理相关的细胞外信号（激素， 代谢物、外源性物质）和细胞内信号传导途径 参与控制有机阴离子转运系统和p- 肾近端小管中的糖蛋白。