Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 45, Pages 17090-17104Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.010320
Keywords
chloride transport; cystic fibrosis transmembrane conductance regulator (CFTR); ion channel; kidney; protein targeting; renal physiology; sodium?proton exchange; sodium channel; epithelial sodium channel (ENaC)
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Funding
- Hopkins Conte Digestive Diseases Basic and Translational Research Core Center
- National Institutes of Health NIDDK [P30DK089502]
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Autosomal-dominant polycystic kidney disease (ADPKD) induces a secretory phenotype, resulting in multiple fluid-filled cysts. We have previously demonstrated that VX-809, a corrector of the cystic fibrosis transmembrane conductance regulator (CFTR), reduces cyst growth. Here, we show that in normal mice CFTR is located within the cells and also at the apical and basolateral membranes. However, in polycystic kidney disease (pkd1)-knockout mice, CFTR was located at the plasma membrane, consistent with its role in cAMP-dependent fluid secretion. In cystic mice, VX-809 treatment increased CFTR levels at the apical membrane and reduced its association with the endoplasmic reticulum. Surprisingly, VX-809 treatment significantly increased CFTR's co-localization with the basolateral membrane in cystic mice. Na+/H+ exchanger 3 (NHE3) is present in pkd1-knockout and normal mice and in proximal tubule-derived, cultured pkd1-knockout cells. VX-809 increased the expression, activity, and apical plasma membrane localization of NHE3. Co-localization of epithelial sodium channel (ENaC) with the plasma membrane was reduced in cysts in pkd1-knockout mice, consistent with an inability of the cysts to absorb fluid. Interestingly, in the cystic mice, VX-809 treatment increased ENaC levels at the apical plasma membrane consistent with fluid absorption. Thus, VX-809 treatment of pkd1-null mouse kidneys significantly affected CFTR, NHE3, and ENaC, altering the cyst phenotype from one poised toward fluid secretion toward one more favorable for absorption. VX-809 also altered the location of CFTR but not of NHE3 or ENaC in normal mice. Given that VX-809 administration is safe, it may have potential utility for treating patients with ADPKD.
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