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Na+/H+ Exchanger Regulatory Factor 3 Is Critical for Multidrug Resistance Protein 4-Mediated Drug Efflux in the Kidney

Title
Na+/H+ Exchanger Regulatory Factor 3 Is Critical for Multidrug Resistance Protein 4-Mediated Drug Efflux in the Kidney
Authors
Park, JoonheeKwak, Jin-OhRiederer, BrigitteSeidler, UrsulaCole, Susan P. C.Lee, Hwa JeongLee, Min Goo
Ewha Authors
이화정
SCOPUS Author ID
이화정scopus
Issue Date
2014
Journal Title
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
ISSN
1046-6673JCR Link1533-3450JCR Link
Citation
vol. 25, no. 4, pp. 726 - 736
Publisher
AMER SOC NEPHROLOGY
Indexed
SCI; SCIE; SCOPUS WOS
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.
DOI
10.1681/ASN.2013040438
Appears in Collections:
약학대학 > 약학과 > Journal papers
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