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Park, Joonhee,Kwak, Jin-Oh,Riederer, Brigitte,Seidler, Ursula,Cole, Susan P.C.,Lee, Hwa Jeong,Lee, Min Goo American Society of Nephrology 2014 Journal of the American Society of Nephrology Vol.25 No.4
<P>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.</P>
Xiao, Fang,Li, Junhua,Singh, Anurag Kumar,Riederer, Brigitte,Wang, Jiang,Sultan, Ayesha,Park, Henry,Lee, Min Goo,Lamprecht, Georg,Scholte, Bob J.,De Jonge, Hugo R.,Seidler, Ursula Blackwell Publishing Ltd 2012 The Journal of physiology Vol.590 No.21
<P><B>Key points</B></P><P><P>Cystic fibrosis (CF) is a lethal disease characterized by low rates of epithelial Cl<SUP>−</SUP> and HCO<SUB>3</SUB><SUP>−</SUP> secretion and obstruction of the airways and gastrointestinal and reproductive organs by sticky mucus. HCO<SUB>3</SUB><SUP>−</SUP> secretion has recently been demonstrated to be necessary for mucus hydration.</P><P>The most frequent CF mutation is F508del. This mutant protein is usually degraded in the proteasome. New therapeutic strategies have been developed which deliver F508del to the plasma membrane.</P><P>Utilizing transgenic F508del mutant and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice, apical membrane expression of F508del protein was found to be associated with enhanced stimulation of intestinal HCO<SUB>3</SUB><SUP>−</SUP> secretion.</P><P>The predominant molecular mechanism for enhanced F508del HCO<SUB>3</SUB><SUP>−</SUP> stimulation appeared to be the activation of a Cl<SUP>−</SUP> recycling pathway, with Cl<SUP>−</SUP> exit via membrane‐resident F508del protein and Cl<SUP>−</SUP> entry in exchange for HCO<SUB>3</SUB><SUP>−</SUP> by apical Cl<SUP>−</SUP>/HCO<SUB>3</SUB><SUP>−</SUP> exchange. In contrast, the predominant molecular mechanism for cAMP‐activated HCO<SUB>3</SUB><SUP>−</SUP> secretion in WT intestine appears to be HCO<SUB>3</SUB><SUP>−</SUP> exit via CFTR itself.</P></P><P><B>Abstract </B> This study investigated whether expression of the common cystic fibrosis transmembrane conductance regulator (CFTR) mutant F508del in the apical membrane of enterocytes confers increased bicarbonate secretory capacity on the intestinal epithelium of F508del mutant mice compared to that of CFTR knockout (KO) mice. CFTR KO mice, F508del mutant mice (F508del) and wild‐type (WT) littermates were bred on the FVB/N background. F508del isolated brush border membrane (BBM) contained approximately 5–10% fully glycosylated band C protein compared to WT BBM. Similarly, the forskolin (FSK)‐induced, CFTR‐dependent short‐circuit current (Δ<I>I</I><SUB>sc</SUB>) of F508del mucosa was approximately 5–10% of WT, whereas the HCO<SUB>3</SUB><SUP>−</SUP> secretory response (<IMG src='/wiley-blackwell_img/equation/TJP_5291_mu1.gif' alt ='inline image'/>) was almost half that of WT in both duodenum and mid‐colon studied <I>in vitro</I> and <I>in vivo.</I> While WT intestine retained full FSK‐induced <IMG src='/wiley-blackwell_img/equation/TJP_5291_mu2.gif' alt ='inline image'/> in the absence of luminal Cl<SUP>−</SUP>, the markedly higher <IMG src='/wiley-blackwell_img/equation/TJP_5291_mu3.gif' alt ='inline image'/> than Δ<I>I</I><SUB>sc</SUB> in F508del intestine was dependent on the presence of luminal Cl<SUP>−</SUP>, and was blocked by CFTR inhibitors. The Ste20‐related proline–alanine‐rich kinases (SPAK/OSR1), which are downstream of the with‐no‐lysine (K) protein kinases (WNK), were rapidly phosphorylated by FSK in WT and F508del, but significantly more slowly in CFTR KO intestine. In conclusion, the data demonstrate that low levels of F508del membrane expression in the intestine of F508del mice significantly increased FSK‐induced HCO<SUB>3</SUB><SUP>−</SUP> secretion mediated by Cl<SUP>−</SUP>/HCO<SUB>3</SUB><SUP>−</SUP> exchange. However, in WT mucosa FSK elicited strong SPAK/OSR1 phosphorylation and Cl<SUP>−</SUP>‐independent HCO<SUB>3</SUB><SUP>−</SUP> efflux. This suggests that therapeutic strategies which deliver F508del to the apical membrane have the potential to significantly enhance epithelial HCO<SUB>3</SUB><SUP>−</SUP> secretion.</P>