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1 Depts of Medicine & Pharmacology, UC San Diego and SDVAHCS, San Diego, California, United States
2 Dept of Medicine, UC San Diego & SDVAHCS, San Diego, California, United States
3 Dept of Pediatrics, UC San Diego, San Diego, California, United States
4 Dept of Medicine, UC San Diego, San Diego, California, United States
5 Depts of Medicine, Pediatrics and Molecular Biology, UC San Diego, La Jolla, California, United States
* To whom correspondence should be addressed. E-mail: vvallon{at}ucsd.edu.
Organic anion transporter genes have been implicated in renal secretion of organic anions, but the individual in vivo contributions of OAT1 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 et al., JBC 2006). Here we show 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 classical basolateral PAH transporter of the proximal tubule, both OAT1 and OAT3 contribute similarly to normal renal secretion of furosemide and bendroflumethiazide, and lack of either one is not fully compensated by the other. While 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.
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