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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/F867    most recent 00528.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vallon, V. Articles by Nigam, S. K. Search for Related Content PubMed PubMed Citation Articles by Vallon, V. Articles by Nigam, S. K.

Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

Division of Nephrology and Hypertension, Departments of ¹Medicine, ²Pharmacology, ³Pediatrics, and ⁴Cellular and Molecular Medicine, University of California, and ⁵Department of Medicine, San Diego Veterans Affairs Healthcare System, La Jolla, California

Submitted 8 November 2007 ; accepted in final form 17 January 2008

Organic anion transporter (OAT) genes have been implicated in renal secretion of organic anions, but the individual in vivo contributions of OAT1 (first identified as NKT) and OAT3 remain unclear. Potential substrates include loop diuretics (e.g., furosemide) and thiazide diuretics (e.g., bendroflumethiazide), which reach their tubular sites of action mainly by proximal tubular secretion. Previous experiments in Oat1 knockout (–/–) mice revealed an almost complete loss of renal secretion of the prototypic organic anion p-aminohippurate (PAH) and a role of OAT1 in tubular secretion of furosemide (Eraly SA, Vallon V, Vaughn D, Gangoiti JA, Richter K, Nagle M, Monte JC, Rieg T, Truong DM, Long JM, Barshop BA, Kaler G, Nigam SK. J Biol Chem 281: 5072–5083, 2006). In this study we found that both furosemide and bendroflumethiazide inhibited mOat1- and mOat3-mediated uptake of a labeled tracer in Xenopus oocytes injected with cRNA, consistent with their being substrates for mouse OAT1 and OAT3. Experiments in Oat3^–/– mice revealed intact renal secretion of PAH, but the dose-natriuresis curves for furosemide and bendroflumethiazide were shifted to the right and urinary furosemide excretion was impaired similar to the defect in Oat1^–/– mice. Thus, whereas OAT1 (in contrast to OAT3) is the classic basolateral PAH transporter of the proximal tubule, both OAT1 and OAT3 contribute similarly to normal renal secretion of furosemide and bendroflumethiazide, and a lack of either one is not fully compensated by the other. Although microarray expression analysis in the kidneys of Oat1^–/– and Oat3^–/– mice revealed somewhat altered expression of a small number of transport-related genes, none were common to both knockout models. When searching for polymorphisms involved in human diuretic responsiveness, it may be necessary to consider both OAT1 and OAT3, among other genes.

organic anion transport; proximal tubule; tubular secretion

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				V. Vallon, S. A. Eraly, W. R. Wikoff, T. Rieg, G. Kaler, D. M. Truong, S.-Y. Ahn, N. R. Mahapatra, S. K. Mahata, J. A. Gangoiti, et al. Organic Anion Transporter 3 Contributes to the Regulation of Blood Pressure J. Am. Soc. Nephrol., September 1, 2008; 19(9): 1732 - 1740. [Abstract] [Full Text] [PDF]

				S. A. Eraly, V. Vallon, T. Rieg, J. A. Gangoiti, W. R. Wikoff, G. Siuzdak, B. A. Barshop, and S. K. Nigam Multiple organic anion transporters contribute to net renal excretion of uric acid Physiol Genomics, April 1, 2008; 33(2): 180 - 192. [Abstract] [Full Text] [PDF]