MECHANISM OF RENAL ORGANIC ANION TRANSPORT

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DESCRIPTION (adapted from the application) This R03 application is linked to grant number K08 DK02492 entitled "Structure/Function study of a Prostaglandin Transporter." This supplemental funding will be applied towards the delineation of the molecular mechanisms of renal organic anion transport through identification of the substrate specificities of a newly identified multi-specific renal organic anion transporter, its structure-function relationships and identification of related transporting polypeptides. The kidney plays a primary role in the elimination of many foreign compounds that enter the body, including environmental xenobiotics and drugs that undergo limited catabolism and are toxic at high levels. In addition, the system is responsible for the excretion of many endogenous, physiologically active compounds. Despite the important role that the renal organic anion secretory system plays in health and disease, there has been little progress in characterizing this system on a molecular level. Para-aminohippurate transport (PAH) transport has been widely studied both as a prototypic organic anion transport process and as a primary means for removal of endogenous compounds and xenobiotics into the urine. The finding that a wide array of these compounds inhibit PAH uptake into the kidney has led to the hypothesis that secreted anions are transported by a single multi-specific transporter. On the other hand, there is evidence suggesting that there are multiple pathways for organic anion secretion. Only direct isolation and characterization of individual transporting polypeptides will answer these questions. The Specific Aims of this research proposal are to: 1) Identify the substrate specificity of the cloned mouse PAH transporter (mPAHT) 2) Determine transmembrane topology of mPAHT using biotin containing sulfhydryl reagents 3) Characterize the substrate binding site and substrate translocation pathway of mPAHT 4) Identify transporting polypeptides related to mPAHT and define their substrate specificities.