Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 303, Issue 8, Pages F1176-F1186Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00130.2012
Keywords
chloride ion channel; autosomal dominant polycystic kidney disease; epithelial ion transport; Madin-Darby canine kidney (MDCK) epithelial cells; small-molecule CFTR modulators
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Funding
- Cystic Fibrosis Trust
- National Kidney Research Fund
- Fundacao para a Ciencia e a Tecnologia (FCT) [POCTI/MGI/47382/2002, SFRH/BPD/19056/2004]
- Nuffield Science Bursary
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/19056/2004, POCTI/MGI/47382/2002] Funding Source: FCT
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Li H, Yang W, Mendes F, Amaral MD, Sheppard DN. Impact of the cystic fibrosis mutation F508del-CFTR on renal cyst formation and growth. Am J Physiol Renal Physiol 303: F1176-F1186, 2012. First published August 8, 2012; doi:10.1152/ajprenal.00130.2012.-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.
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