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).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
1P01DK041006-01A1
Application #
3095565
Study Section
Diabetes and Digestive and Kidney Diseases Special Grants Review Committee (DDK)
Project Start
1989-08-01
Project End
1994-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85722
Dantzler, W H; Evans, K K (1996) Effect of alpha-KG in lumen on PAH transport by isolated perfused rabbit renal proximal tubules. Am J Physiol 271:F521-6
Villalobos, A R; Braun, E J (1995) Characterization of organic cation transport by avian renal brush-border membrane vesicles. Am J Physiol 269:R1050-9
Wright, S H; Wunz, T M; Wunz, T P (1995) Structure and interaction of inhibitors with the TEA/H+ exchanger of rabbit renal brush border membranes. Pflugers Arch 429:313-24
Groves, C E; Wright, S H (1995) Tetrapentylammonium (TPeA): slowly dissociating inhibitor of the renal peritubular organic cation transporter. Biochim Biophys Acta 1234:37-42
Kim, Y K; Dantzler, W H (1995) Intracellular pH in snake renal proximal tubules. Am J Physiol 269:R822-9
Groves, C E; Morales, M N; Gandolfi, A J et al. (1995) Peritubular paraquat transport in isolated renal proximal tubules. J Pharmacol Exp Ther 275:926-32
Shpun, S; Evans, K K; Dantzler, W H (1995) Interaction of alpha-KG with basolateral organic anion transporter in isolated rabbit renal S3 proximal tubules. Am J Physiol 268:F1109-16
Wright, S H; Wunz, T M (1995) Paraquat2+/H+ exchange in isolated renal brush-border membrane vesicles. Biochim Biophys Acta 1240:18-24
Dantzler, W H; Evans, K K; Wright, S H (1995) Kinetics of interactions of para-aminohippurate, probenecid, cysteine conjugates and N-acetyl cysteine conjugates with basolateral organic anion transporter in isolated rabbit proximal renal tubules. J Pharmacol Exp Ther 272:663-72
Fisher, R L; Sanuik, J T; Gandolfi, A J et al. (1994) Toxicity of cisplatin and mercuric chloride in human kidney cortical slices. Hum Exp Toxicol 13:517-23

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