title: Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice.
abstract: To begin to develop in vivo model systems for the assessment of the contributions of specific organic anion transporter (OAT) family members to detoxification, development, and disease, we carried out a targeted disruption of the murine organic anion transporter 3 (Oat3) gene. Surviving Oat3(-/-) animals appear healthy, are fertile, and do not exhibit any gross morphological tissue abnormalities. No Oat3 mRNA expression was detected in kidney, liver, or choroid plexus (CP) of Oat3(-/-) mice. A distinct phenotype manifested by a substantial loss of organic anion transport capacity in kidney and CP was identified. Uptake sensitive to inhibition by bromosulfophthalein or probenecid was observed for taurocholate, estrone sulfate, and para-aminohippurate in renal slices from wild-type mice, whereas in Oat3(-/-) animals transport of these substances was greatly reduced. No discernable differences in uptake were observed between hepatic slices from wild-type and Oat3(-/-) littermates, suggesting Oat3 does not play a major role in hepatic organic anion uptake. Cellular accumulation of fluorescein was reduced by approximately 75% in CP from Oat3(-/-) mice. However, capillary accumulation of fluorescein-methotrexate was unchanged, indicating the effects of Oat3 loss are restricted to the entry step and that Oat3 is localized to the apical membrane of CP. These data indicate a key role for Oat3 in systemic detoxification and in control of the organic anion distribution in cerebrospinal fluid.
authors: Department of Pediatrics, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors: Douglas H
authors: DH
authors: Sweet
authors: David S
authors: DS
authors: Miller
authors: John B
authors: JB
authors: Pritchard
authors: Yuko
authors: Y
authors: Fujiwara
authors: David R
authors: DR
authors: Beier
authors: Sanjay K
authors: SK
authors: Nigam
mesh_terms: D000818:Animals; D000838:Anions; D001692:Biological Transport; D015152:Blotting, Northern; D001921:Brain / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000378:metabolism; D002831:Choroid Plexus / Q000378:metabolism; D003001:Cloning, Molecular; D004970:Estrone / Q000031:analogs & derivatives* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008957:Models, Genetic; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D010641:Phenotype; D011339:Probenecid / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013448:Sulfobromophthalein / Q000493:pharmacokinetics; D013656:Taurocholic Acid / Q000378:metabolism; D014981:Xenopus; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D000838:Anions; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C114338:organic anion transport protein 3; D013448:Sulfobromophthalein; D004970:Estrone; D013656:Taurocholic Acid; D011339:Probenecid; C017296:estrone sulfate; D010130:p-Aminohippuric Acid