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

Authors
 Joonhee Park  ;  Jin-Oh Kwak  ;  Brigitte Riederer  ;  Ursula Seidler  ;  Susan P.C. Cole  ;  Hwa Jeong Lee  ;  Min Goo Lee 
Citation
 Journal of the American Society of Nephrology, Vol.25(4) : 726-736, 2014 
Journal Title
 Journal of the American Society of Nephrology 
ISSN
 1046-6673 
Issue Date
2014
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.
Full Text
http://jasn.asnjournals.org/content/25/4/726.long
DOI
10.1681/ASN.2013040438
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
박준희(Park, Joonhee)
이민구(Lee, Min Goo) ORCID logo https://orcid.org/0000-0001-7436-012X
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/98375
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