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.
Highlights
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
Oat3 Loss Impairs Transport in Kidney and Choroid Plexus are located in the apical membrane in proximal tubule; human OAT3 has recently been localized to the basolateral membrane by immunocytochemistry [25]
Data were calculated as tissue to medium T/M ratios and are presented as mean values Ϯ S.E. (3 slices/treatment)
Summary
Vol 277, No 30, Issue of July 26, pp. 26934 –26943, 2002 Printed in U.S.A. Impaired Organic Anion Transport in Kidney and Choroid Plexus of Organic Anion Transporter 3 (Oat (Slc22a8)) Knockout Mice*. The resultant Oat3Ϫ/Ϫ mice are fertile and exhibit no obvious morphological defects, but present a distinct physiological phenotype measurable as impaired organic anion transport function in renal and choroid plexus epithelia. This reduced transport capacity indicates that Oat plays an essential role in the disposition of organic anions in the general circulation and in the extracellular environment of the brain
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