TRANSPORT CHARACTERISTICS IN SPECIFIC RENAL CELL TYPES

我们建议对有机阳离子的转运机制(S)进行研究。 肾近端小管。有机阳离子(延伸为有机阳离子 碱基；OC)代表一组不同的生理上重要的 化合物，包括胆碱、肾上腺素和 N-甲基烟酰胺(NMN)。OC还包括一些药物，如 西咪替丁、普鲁卡因胺和四乙基铵(TEA)。这一过程 肾小管分泌和重吸收被认为起重要作用 在调节许多这类药物的血浆浓度方面的作用 化合物。然而，人们对其发病机制知之甚少。 OC的管状转运。目前有相互矛盾的证据 关于负责跨上皮的过程的性质 OC的运输；一些研究表明，OC的管腔膜 近端肾小管上皮细胞在OC分泌中起积极作用，而近端肾小管上皮细胞 肾小管膜起被动作用；其他数据表明 肾小管膜是OC主动转运的部位，而肾小管上皮细胞 腔膜是被动的。我们有初步数据显示， 兔近端小管的管腔膜和管周膜有 主动的运输过程，有助于促进 我们建议扩展这些研究的范围，以研究使用 几种不同的蜂窝组织“级别”，每一种都提供 研究输运过程的独特优势：i)孤立 膜，它允许对动力学机制进行详细检查 在严格控制的条件下，大规模筛选 结构特异性研究中的许多化合物；ii)分离的细胞和 小管，允许同时检查运输 管腔膜和管周膜的作用，以及 运输和新陈代谢之间的联系的研究；以及iii)近端的血流 小管，它提供了研究管腔和管周的机会 输送串联工作，以产生跨上皮通量。这个 综合使用这三种方法将使我们能够制定和 检验有关近端小管OC发病机制的详细假说 运输。我们希望开发一种肾小管OC转运模型 这两种方法都有助于理解肾脏在调节 这些化合物的血浆水平，并增加我们对 上皮性分泌过程。

We propose to study the mechanism(s) of organic cation transport in thearenal proximal tubule. Organic cations (and by extension, organic bases; OC's) represent a diverse set of physiologically important compounds, including molecules such as choline, epinephrine, and N1-methylnicotinamide (NMN). OC's also include a number of drugs, such as cimetidine, procainamide, and tetraethylammonium(TEA). The processes of renal tubular secretion and reabsorption are presumed to play an important role in regulating the plasma concentration of a number of these compounds. However, comparatively little is known about the mechanism of tubular transport of OC's. Currently there is conflicting evidence concerning the nature of the processes responsible for the transepithelial transport of OC's; some studies suggest that the lumenal membrane of the proximal tubular cell plays the active role in OC secretion, while the pertubular membrane play a passive role; other data suggest that the pertubular membrane is the site of active OC transport, and that the lumenal membrane is passive. We have preliminary data suggesting that both the lumenal and peritubular membranes of the rabbit proximal tubule have active transport processes which serve to facilitate the secretion of OC's. We propose to extend these studies by examining OC transport using several different "levels" of cellular organization, each of which offers unique advantages to the study of transport processes: i) isolated membranes, which permit both the detailed examination of kinetic mechanisms under carefully controlled conditions, and the large-scale screening of many compounds in studies of structural specificity; ii) isolated cells and tubules, which permit simultaneous examination of the transport contributions of both lumenal and peritubular membranes, as well as the study of links between transport and metabolism; and iii) perfused proximal tubules, which offer the opportunity to study lumenal and peritubular transport working in series to produce transepithelial fluxes. The integrated use of these three methodologies will permit us to formulate and test detailed hypotheses concerning the mechanism of proximal tubular OC transport. We hope to develop a model for renal tubular OC transport that will both aid in understanding the role of the kidney in regulation of plasma levels of these compounds, and increase our general understanding of epithelial secretory processes.