In
autosomal dominant polycystic kidney disease (
ADPKD),
cystic fibrosis transmembrane conductance regulator (CFTR), the
protein product of the gene defective in
cystic fibrosis (CF), plays a crucial role in fluid accumulation, which promotes
cyst swelling. Several studies have identified individuals afflicted by both
ADPKD and CF. Two studies suggested that CF mutations might attenuate the severity of
ADPKD, whereas a third found no evidence of a protective effect. In this study, we investigated the impact of the commonest CF mutation F508del-CFTR on the formation and growth of renal
cysts. As a model system, we used Madin-Darby canine kidney (MDCK) epithelial cells engineered to express wild-type and F508del human CFTR. We grew MDCK
cysts in
collagen gels in the presence of the cAMP agonist
forskolin and measured transepithelial resistance and Cl(-) secretion with the Ussing chamber technique and assayed cell proliferation using nonpolarized MDCK cells. When compared with untransfected MDCK cells, cells expressing wild-type CFTR generated substantial numbers of large
cysts, which grew markedly over time. By contrast, MDCK cells expressing F508del-CFTR formed very few tiny
cysts that failed to enlarge. Interestingly, treatment of F508del-CFTR
cysts with the CFTR corrector
VRT-325 and the CFTR corrector-potentiator
VRT-532 increased the number, but not size, of F508del-CFTR
cysts, possibly because
VRT-325 inhibited strongly cell proliferation. Based on its effects on transepithelial resistance, Cl(-) secretion, and cell proliferation, we conclude that the F508del-CFTR mutation disrupts
cyst formation and growth by perturbing strongly fluid accumulation within the
cyst lumen without compromising epithelial integrity.