The kidney is the principal means for excretion from the body of a vast array of anionic compounds of physiological, pharmacological and toxicological significance (including p-lactam antibiotics;nucleoside- derived antiviral compounds;non-steroidal anti-inflammatory drugs (NSAIDs);and anionic chelators and chelates of heavy metals). In addition, the kidney plays a critical auxiliary role with the liver in controlling plasma levels of many other anionic metabolites of Phase II metabolism. Renal excretion of these organic anions (OAs) is dominated by the processes of transepithelial secretion mediated by cells of the renal proximal tubule (RPT). In recent years, increasing evidence supports the contention that renal secretion of OAs involves the concerted activity of many separate transport proteins that are expressed in the basolateral (peritubular) and apical (luminal) membranes of RPTs. Although the basolateral 'entry step'is now reasonably well understood, the luminal membrane of the RPT represents 'the dark side of the moon'with respect to our understanding of renal OA secretion. Despite the fact that at least 8 distinct transporters have been shown to be expressed in the luminal membrane of RPT for none of these potential 'candidate'luminal transporters is the extent of their influence on renal OAsecretion understood. The experiments proposed here represent an integrated program of study designed to establish the contribution to renal OA secretion of one group of luminal transporters, i.e., the multidrug resistance-associate proteins (the MRPs). We combine the use of cloned transport proteins and model cultured cell systems with studies that employ intact renal tubules and intact animals. We will develop model systems that cultured cells expressing cloned transport proteins to assess the relative contribution to secretion of two distinct basolateral 'organic anion transporters'transporters (OATs;i.e., OAT1 and OAT3) and two distinct luminal transporters (i.e., MRP2 and MRP4). These model cells will provide data required to design and interpret experiments using isolated single renal proximal tubules and whole renal clearance measurements that employ both wild type mice and genetic models that lack selected OA transporters. The innovative design of this research program permits assessment of the mechanistic basis of secretion at three distinct levels of biological organization: the molecular and cellular;the epithelial/tissue;and the whole orsan/oreanismic, and will develop for the first time a view of the potential role of both luminal and basolateral events in drue-drua interactions and the development of nephrotoxicity.
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