Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 19, Issue 9, Pages 1732-1740Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2008020180
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [DK56248, DK28602, DK064839, DK075486, AI057695, DK079784, HL35018]
- Department of Veterans Affairs
- Deutsche Forschungsgemeinschaft [RI 1535/3-1, RI 1535/3-2]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL035018] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI057695] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK079784, R03DK075486, K08DK064839, R01DK028602, R01DK056248] Funding Source: NIH RePORTER
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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.
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