Received February 13, 2008
Accepted on April 11, 2008

BASIC RESEARCH

Organic Anion Transporter 3 Contributes to the Regulation of Blood Pressure

Volker Vallon ^*1, Satish A. Eraly ^*, William R. Wikoff , Timo Rieg ^*, Gregory Kaler ^*, David M. Truong ^*, Sun-Young Ahn ^*, Nitish R. Mahapatra ^*, Sushil K. Mahata ^*, Jon A. Gangoiti ^||, Wei Wu ^*, Bruce A. Barshop ^||, Gary Siuzdak , and Sanjay K. Nigam ^*||¶1

Departments of *Medicine, Pharmacology, ||Pediatrics, and ¶Cellular and Molecular Medicine, University of California, San Diego, Department of Medicine, San Diego VA Healthcare System, and Department of Molecular Biology and the Center for Mass Spectrometry, Scripps Research Institute, La Jolla, California

¹ To whom correspondence should be addressed. E-mail: vvallon{at}ucsd.edu.

	Abstract

Renal organic anion transporters (OAT) are known to mediate the excretion of many drugs, but their function in normal physiology is not well understood. In this study, mice lacking organic anion transporter 3 (Oat3) had a 10 to 15% lower BP than wild-type mice, raising the possibility that Oat3 transports an endogenous regulator of BP. The aldosterone response to a low-salt diet was blunted in Oat3-null mice, but baseline aldosterone concentration was higher in these mice, suggesting that aldosterone dysregulation does not fully explain the lower BP in the basal state; therefore, both targeted and global metabolomic analyses of plasma and urine were performed, and several potential endogenous substrates of Oat3 were found to accumulate in the plasma of Oat3-null mice. One of these substrates, thymidine, was transported by Oat3 expressed in vitro. In vivo, thymidine, as well as two of the most potent Oat3 inhibitors that were characterized, reduced BP by 10 to 15%; therefore, Oat3 seems to regulate BP, and Oat3 inhibitors might be therapeutically useful antihypertensive agents. Moreover, polymorphisms in human OAT3 might contribute to the genetic variation in susceptibility to hypertension.