title: The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP.
abstract: The cyclic nucleotides cAMP and cGMP play key roles in cellular signaling and the extracellular regulation of fluid balance. In the kidney, cAMP is excreted across the apical proximal tubular membrane into urine, where it reduces phosphate reabsorption through a dipyridamole-sensitive mechanism that is not fully understood. It has long been known that this cAMP efflux pathway is dependent on ATP and is inhibited by probenecid. However, its identity and whether cGMP shares the same transporter have not been established. Here the expression, localization, and functional properties of human multidrug resistance protein 4 (MRP4) are reported. MRP4 is localized to the proximal tubule apical membrane of human kidney, and membrane vesicles from Sf9 cells expressing human MRP4 exhibit ATP-dependent transport of [(3)H]cAMP and [(3)H]cGMP. Both probenecid and dipyridamole are potent MRP4 inhibitors. ATP-dependent [(3)H]methotrexate and [(3)H]estradiol-17beta-D-glucuronide transport by MRP4 and interactions with the anionic conjugates S-(2,4-dinitrophenyl)-glutathione, N-acetyl-(2,4-dinitrophenyl)-cysteine, alpha-naphthyl-beta-D-glucuronide, and p-nitrophenyl-beta-D-glucuronide are also demonstrated. In kidneys of rats deficient in the apical anionic conjugate efflux pump Mrp2, Mrp4 expression is maintained at the same level. It is concluded that MRP4 is a novel apical organic anion transporter and the putative efflux pump for cAMP and cGMP in human kidney proximal tubules.
authors.affiliation: Departments of *Pharmacology and Toxicology and Cell Physiology, Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Rémon A M H
authors.initials: RAMH
authors.lastname: van Aubel
authors.affiliation: Departments of *Pharmacology and Toxicology and Cell Physiology, Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Pascal H E
authors.initials: PHE
authors.lastname: Smeets
authors.affiliation: Departments of *Pharmacology and Toxicology and Cell Physiology, Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Janny G P
authors.initials: JGP
authors.lastname: Peters
authors.affiliation: Departments of *Pharmacology and Toxicology and Cell Physiology, Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: René J M
authors.initials: RJM
authors.lastname: Bindels
authors.affiliation: Departments of *Pharmacology and Toxicology and Cell Physiology, Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Frans G M
authors.initials: FGM
authors.lastname: Russel
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism* / Q000652:urine; D006152:Cyclic GMP / Q000378:metabolism* / Q000652:urine; D004958:Estradiol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007150:Immunohistochemistry; D007313:Insecta / Q000166:cytology; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008727:Methotrexate / Q000493:pharmacokinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000502:physiology*; D027361:Organic Anion Transporters / Q000502:physiology*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D006152:Cyclic GMP; D004958:Estradiol; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; C073492:ABCC4 protein, human; C489542:Abcc4 protein, rat; C025483:estradiol-17 beta-glucuronide