The long-term objectives of this Program Project are to understand- 1) the mechanisms involved in renal tubular transport of organic cations (or bases), 2) the mechanisms involved in renal tubular transport of organic anions (or acids), particularly the transport of uric acid in relation to stone formation; 3) the regulation of physiologically and pharmacologically important molecules transported by these pathways; 4) the possible toxic effects of molecules transported by these pathways; and 5) the processes by which renal toxicants interfere with these pathways. The research strategy involves an integrated approach among four individual projects using systems that represent different levels of biological organization -- from the whole animal to the cell membrane -- and using a wide variety of techniques. Several species (or tissue from several species) of mammalian--rabbit, rat, and pig and nonmammalian-- snake and chicken -- species will be employed to take advantage of exaggerated function or ease of preparation in different species. Specific preparations, reflecting levels of biological organization, to be used are whole animals (Projects #2 and #4), kidney slices (Project #3), isolated renal tubules (Projects 01, *2, *3, and *4), renal cells in culture (Projects *2 and *3), and renal membrane vesicles (Projects 01, 02, and 04). Major techniques or experimental designs linking the projects include: clearance studies (Projects #2 and *4); radiotracer studies of transport (Projects *I, *2, *3, and #4); histological, histochemical, and ultrastructural analyses of transport or toxicity (Projects 03 and 04); measurements of intracellular concentrations of organic ions by isotopic labeling techniques (Projects *1, *2, and *3) and of intracellular activities by ion-selective microelectrodes (Projects *1 and *2); optical procedures for measuring transport and intracellular pH and pCa (Projects *I, *2, and *3); and the use of compounds with different chemical structures for probing the specificity and chemical structure of the carriers and for isolating and identifying them (Projects *1 and *2) or for probing specificity of toxic effects (Projects 01, 02, and *3).
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