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.
| Wright, S H; Wunz, T M (1989) Amiloride transport in rabbit renal brush-border membrane vesicles. Am J Physiol 256:F462-8 |
| Dantzler, W H; Brokl, O H; Wright, S H (1989) Brush-border TEA transport in intact proximal tubules and isolated membrane vesicles. Am J Physiol 256:F290-7 |
| Wright, S H; Wunz, T M (1988) Mechanism of cis- and trans-substrate interactions at the tetraethylammonium/H+ exchanger of rabbit renal brush-border membrane vesicles. J Biol Chem 263:19494-7 |
