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Papers In Press, published online ahead of print December 14, 2005
Medicine Dept., University of California, San Diego, San Diego, CA 92126
Corresponding Author: saeraly{at}hotmail.com
The “classical” organic anion secretory pathway of the renal proximal tubule is critical for the renal excretion of a large number of commonly prescribed drugs among other significant substrates. Organic anion transporter 1 (OAT1/NKT (1)) is expressed in the proximal tubule and has been shown to transport many of the classical pathway substrates in vitro, in particular, the prototypic substrate, para-aminohippurate (PAH). Thus, OAT1 has physiological properties consistent with a role in this pathway. However, several other transporters (e.g., OAT2, OAT3, MRP1) have also been proposed as important PAH transporters on the basis of in vitro studies – therefore, the relative contribution of OAT1 has remained unclear. We have now generated a colony of OAT1 knockout mice, permitting elucidation of the role of OAT1 in the context of these other potentially functionally redundant transporters. We find that the knockout mice manifest a profound loss of organic anion transport both ex vivo (in isolated renal slices) as well as in vivo (as indicated by loss of renal secretion). In the case of the organic anion, furosemide, loss of renal secretion in the knockout results in impaired diuretic responsiveness to this drug. These results indicate a critical role for OAT1 in the functioning of the classical pathway. In addition, we have determined the levels of ~60 endogenous organic anions in the plasma and urine of wild-type and knockout mice. This has led to identification of several compounds with significantly higher plasma concentrations and/or lower urinary concentrations in knockout mice, suggesting the involvement of OAT1 in their renal secretion. Importantly, we have demonstrated that some of these compounds interact with OAT1 in vitro. Thus, these latter compounds might represent physiological substrates of OAT1.
J. Biol. Chem, 10.1074/jbc.M508050200
Submitted on July 22, 2005
Accepted on December 14, 2005
Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knockout mice
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