title: Na⁺/H⁺ exchanger regulatory factor 3 is critical for multidrug resistance protein 4-mediated drug efflux in the kidney.
abstract: Na(+)/H(+) exchanger regulatory factor 3 (NHERF3) is a PSD-95/discs large/ZO-1 (PDZ)-based adaptor protein that regulates several membrane-transporting proteins in epithelia. However, the in vivo physiologic role of NHERF3 in transepithelial transport remains poorly understood. Multidrug resistance protein 4 (MRP4) is an ATP binding cassette transporter that mediates the efflux of organic molecules, such as nucleoside analogs, in the gastrointestinal and renal epithelia. Here, we report that Nherf3 knockout (Nherf3(-/-)) mice exhibit profound reductions in Mrp4 expression and Mrp4-mediated drug transport in the kidney. A search for the binding partners of the COOH-terminal PDZ binding motif of MRP4 among several epithelial PDZ proteins indicated that MRP4 associated most strongly with NHERF3. When expressed in HEK293 cells, NHERF3 increased membrane expression of MRP4 by reducing internalization of cell surface MRP4 and consequently, augmented MRP4-mediated efflux of adefovir, a nucleoside-based antiviral agent and well known substrate of MRP4. Examination of wild-type and Nherf3(-/-) mice revealed that Nherf3 is most abundantly expressed in the kidney and has a prominent role in modulating Mrp4 levels. Deletion of Nherf3 in mice caused a profound reduction in Mrp4 expression at the apical membrane of renal proximal tubules and evoked a significant increase in the plasma and kidney concentrations of adefovir, with a corresponding decrease in the systemic clearance of this drug. These results suggest that NHERF3 is a key regulator of organic transport in the kidney, particularly MRP4-mediated clearance of drug molecules.
authors.affiliation: Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea;
authors.forename: Joonhee
authors.initials: J
authors.lastname: Park
authors.forename: Jin-Oh
authors.initials: JO
authors.lastname: Kwak
authors.forename: Brigitte
authors.initials: B
authors.lastname: Riederer
authors.forename: Ursula
authors.initials: U
authors.lastname: Seidler
authors.forename: Susan P C
authors.initials: SP
authors.lastname: Cole
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000225:Adenine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D063065:Organophosphonates / Q000493:pharmacokinetics; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000225:Adenine; D002352:Carrier Proteins; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D063065:Organophosphonates; C073492:ABCC4 protein, human; C489540:Abcc4 protein, mouse; C484659:PDZK1 protein, human; C053001:adefovir