Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice.
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.
Sweet
Douglas H
DH
Department of Pediatrics, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Miller
David S
DS
Pritchard
John B
JB
Fujiwara
Yuko
Y
Beier
David R
DR
Nigam
Sanjay K
SK
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
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