Renal excretion of a wide variety of anionic organic compounds of physiological, pharmacological, and toxicological importance is accomplished primarily through active secretion by the renal proximal tubule (RPT). OA secretion by the RPT is accomplished by uptake across the basolateral membrane and efflux across the apical membrane, and many transporters have been implicated in mediating both steps. The cellular and molecular physiology of the basolateral uptake step is well defined, involving the activities of the transporters OAT1 and OATS. In contrast, virtually nothing is known about the molecular and cellular physiology of the apical efflux step. The three specific aims outlined in this proposal make use of cloned proteins isolated in model cell systems, and are designed to test the hypothesis that MRP2 and MRP4, both of which are localized to the apical membrane of RPT cells, contribute to the secretion of OAs primarily excreted by the kidney (e.g., B-lactam antibiotics and antiviral nucleoside derivatives). Importantly, these studies will provide a view of the potential role of luminal events in drug-drug interactions and the development of nephrotoxicity, making it important work for improving overall health. ? ? ?
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