Na^+ -sensitive hypertension is related to an alteration of Na^+ absorption in the kidney. Milan Hypertensive Rats (MNS), an animal model for this pathology, are characterized by a raise of Na,K ATPase activity, due to a mutation of the cytoskeletal protein adducin, whose mutations cause hypertension in humans too. Patch-clamp experiments on MHS and MNS DCT cells revealed the activity of a small conductance, voltage independent Cl- channel with the same biophysical characteristics of CFTR; it was inhibited by CFTR(inh)-172 and activated by forskolin, proving this channel to be a CFTR. Density and activity were significantly increased in MHS rats. As CFTR is influenced by cytoskeletal proteins, we tested the effect on CFTR of wild-type and hypertension-related G460W adducin variant. Patch-clamp, FRET and Western blot experiments were performed on HEK cells stably transfected with wild-type (NU12) and G460W adducin (HU33) and expressing CFTR. We demonstrated a direct interaction between CFTR and adducin. In whole-cell experiments, both the CFTR chloride current and the slope of current activation after forskolin addition were significantly higher in HU cells. A higher plasmamembrane density of active CFTR in HU cells was confirmed by means of cell-attached. Western blots revealed an increased expression of CFTR in HU cells. Alteration of CFTR activity could have consequences that could contribute to the functional alteration of kidney cell during Na^+-sensitive hypertension.