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The pathogenic mechanism of cystic fibrosis (CF) includes the functional interaction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein with the epithelial sodium channel (ENaC). The reduction of ENaC activity may constitute a therapeutic option for CF. This hypothesis was evaluated using drugs that target the protease-dependent activation of the ENaC channel and the transcriptional activity of its coding genes. To this aim we used: camostat, a protease inhibitor; S-adenosyl methionine (SAM), showed to induce DNA hypermethylation; curcumin, known to produce chromatin condensation. SAM and camostat are drugs already clinically used in other pathologies, while curcumin is a common dietary compound. The experimental systems used were CF and non-CF immortalized human bronchial epithelial cell lines as well as human bronchial primary epithelial cells. ENaC activity and  SCNN1A ,  SCNN1B  and  SCNN1G  gene expression were analyzed, in addition to  SCNN1B  promoter methylation. In both immortalized and primary cells, the inhibition of extracellular peptidases and the epigenetic manipulations reduced ENaC activity. Notably, the reduction in primary cells was much more effective. The  SCNN1B  appeared to be the best target to reduce ENaC activity, in respect to  SCNN1A  and  SCNN1G . Indeed, SAM treatment resulted to be effective in inducing hypermethylation of  SCNN1B  gene promoter and in lowering its expression. Importantly, CFTR expression was unaffected, or even upregulated, after treatments. These results open the possibility of CF patients’ treatment by epigenetic targeting.

Downregulation of epithelial sodium channel (ENaC) activity in cystic fibrosis cells by epigenetic targeting