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Kidney Week

Abstract: TH-PO682

A Strategy for Reducing Cysts in Autosomal Dominant Polycystic Kidney Disease with a CFTR Corrector

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


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

ADPKD is associated with progressive enlargement of cysts. Mutations in pkd1 and pkd2 induce growth-related pathways, including heat shock proteins raising the prospect that pharmacological interventions that target these pathways might alleviate or prevent ADPKD. The purpose of our study was to demonstrate a role for VX-809, a corrector of cystic fibrosis transmembrane conductance regulator (CFTR), in reducing cyst growth.


We used the Pkd1fl/fl; Pax8rtTA; TetO-cre mouse model which, when treated with doxycycline, allows for the ablation of PC1. These mice, where injected IP with doxycycline (4 µg of doxycycline/g body weight) on postnatal days (PND)11, PND12, and PND13, to induce multiple large cysts and large polycystic kidneys at approximately 3 weeks of age. Kidneys were harvested, sectioned and analyzed.


Mice injected daily with VX-809 (30 mg/kg) from PND10 to PND20 showed significantly less cyst growth (see Fig 1). VX-809 improved renal function, as evidenced by a lower blood urea nitrogen (BUN) and creatinine. In proximal tubule-derived, Pkd1-knockout cells and in cystic kidneys, VX-809 reduced both basal and forskolin-activated cAMP levels, inhibited cyst growth and reduced levels of the heat shock proteins Hsp27, 70, and 90 which are upregulated in cystic kidneys. In the cystic mice, VX-809 decreased an ER stress marker, the GADD153 protein, cell proliferation, and apoptosis. Importantly in proximal tubule-derived, cultured Pkd1-knockout cells, VX-809 increased the activity of the sodium proton exchanger, NHE3 which is down regulated in these cells.


VX-809 reduces the ability of cysts to grow by reducing the levels of HSPs and restore the NHE3 activity in proximal tubule cells. VX-809 could potentially be a new way to treat patients with ADPKD.

Fig. 1: Cystic mice kidneys before and after treatment with VX-809. See text for details.