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J. Biol. Chem., Vol. 281, Issue 8, 5072-5083, February 24, 2006

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Decreased Renal Organic Anion Secretion and Plasma Accumulation of Endogenous Organic Anions in OAT1 Knock-out Mice^*

Satish A. Eraly, Volker Vallon^¶, Duke A. Vaughn, Jon A. Gangoiti^||, Kerstin Richter^¶, Megha Nagle, Julio C. Monte, Timo Rieg^¶, David M. Truong, Jeffrey M. Long^||, Bruce A. Barshop^||, Gregory Kaler, and Sanjay K. Nigam^||**1

From the Departments of Medicine, Pharmacology, ^||Pediatrics, and ^**Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093 and the ^¶Department of Medicine, San Diego Veterans Affairs Healthcare System, San Diego, California 92161

The "classical" organic anion secretory pathway of the renal proximal tubule is critical for the renal excretion of the prototypic organic anion, para-aminohippurate, as well as of a large number of commonly prescribed drugs among other significant substrates. Organic anion transporter 1 (OAT1), originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J. G., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471–6478), has physiological properties consistent with a role in this pathway. However, several other transporters (e.g. OAT2, OAT3, and 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 knock-out mice, permitting elucidation of the role of OAT1 in the context of these other potentially functionally redundant transporters. We find that the knock-out mice manifest a profound loss of organic anion transport (e.g. para-aminohippurate) 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 knock-out 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 knock-out mice. This has led to identification of several compounds with significantly higher plasma concentrations and/or lower urinary concentrations in knock-out mice, suggesting the involvement of OAT1 in their renal secretion. We have also demonstrated in xenopus oocytes that some of these compounds interact with OAT1 in vitro. Thus, these latter compounds might represent physiological substrates of OAT1.

Received for publication, July 22, 2005 , and in revised form, October 20, 2005.

^* This work was supported by NICHHD, National Institutes of Health (NIH), Grant HD40011 and AI057695 (to S. K. N.); NIDDK (NIH) Grants DK064839 (to S. A. E.) and DK56248 and DK28602 (to V. V.); Deutsche Forschungsgemeinschaft Grant RI 1535/3-1 (to T. R.); and the Department of Veterans Affairs (to V. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093. Tel.: 858-822-3482; Fax: 858-822-3483; E-mail: snigam{at}ucsd.edu.

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