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Kidney Week

Abstract: FR-PO719

Correcting the Trafficking of CFTR, NHE3, and ENaC in ADPKD Reduces Cysts and Improves Renal Function

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Yanda, Murali K., Johns Hopkins School of Medicine, Baltimore, Maryland, United States
  • Cebotaru, Liudmila, Johns Hopkins School of Medicine, Baltimore, Maryland, United States

Autosomal dominant polycystic kidney disease (ADPKD), caused by malfunction of either PC1 or 2, is associated with progressive enlargement of cysts, leading to a decline in function and renal failure. We demonstrated previously that VX-809, a CFTR corrector, used to rescue CFTR trafficking, reduces cyst growth in mouse models.


To address the mechanism of how this occurs, we used proximal tubule-derived, cultured Pkd1-knockout cells and the Pkd1fl/fl; Pax8rtTA; TetO-cre mouse model. Treating the mice with doxycycline (doxy), ablates PC1 in renal tubular epithelial cells and causes the development of multiple large cysts which leads to a decline in renal function .


We found that cysts are reduced when the mice are treated with VX-809 and renal function improved. VX-809 treatment of cultured Pkd1-knockout cells increased the activity of NHE3. We assessed the location of NHE3 and ENaC in the cystic kidneys using confocal microscopy. In the mice treated with doxy, NHE3 and ENaC were present in large cysts, but not at the apical membrane. NHE3 and ENaC primarily colocalized with Rab11, a marker of recycling endosomes. In the mice treated with doxy and VX-809, NHE3 and ENaC colocalized with a plasma membrane marker consistent with an increase in NHE3 and ENaC activity and protein expression. In the mice were treated with doxy large cysts developed and the CFTR was colocalized with the ER marker, and to a small amount with apical membrane marker. When mice were treated with doxy and VX-809, most of the CFTR was rescued from the ER and colocalized with the basolateral membrane (Fig.1) and total protein levels increased. Interestingly, basolateral localization of CFTR occurs in the sweat duct, a normally Cl- absorbing epithelium.


The data suggest that VX-809 reduces cyst size in the PC1-null mice by promoting an absorptive phenotype. Given that administration of VX-809 is safe, this drug potentially offers a new way to treat patients with ADPKD.