The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP.

Article Details

Citation

van Aubel RA, Smeets PH, Peters JG, Bindels RJ, Russel FG

The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP.

J Am Soc Nephrol. 2002 Mar;13(3):595-603.

PubMed ID
11856762 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
Cyclic adenosine monophosphateMultidrug resistance-associated protein 4ProteinHumans
Unknown
Substrate
Inhibitor
Details
DipyridamoleMultidrug resistance-associated protein 4ProteinHumans
Unknown
Inhibitor
Details
MethotrexateMultidrug resistance-associated protein 4ProteinHumans
Unknown
Substrate
Inhibitor
Details
ProbenecidMultidrug resistance-associated protein 4ProteinHumans
Unknown
Inhibitor
Details