CFTR null mutation altered cAMP-sensitive and swelling-activated Cl−currents in primary cultures of mouse nephron

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Abstract
The role of cystic fibrosis transmembrane conductance regulator (CFTR) in the control of Cl−currents was studied in mouse kidney. Whole cell clamp was used to analyze Cl−currents in primary cultures of proximal and distal convoluted and cortical collecting tubules from wild-type (WT) and cftr knockout (KO) mice. In WT mice, forskolin activated a linear Cl−current only in distal convoluted and cortical collecting tubule cells. This current was not recorded in KO mice. In both mice, Ca2+-dependent Cl−currents were recorded in all segments. In WT mice, volume-sensitive Cl−currents were implicated in regulatory volume decrease during hypotonicity. In KO mice, regulatory volume decrease and swelling-activated Cl−current were impaired but were restored by adenosine perfusion. Extracellular ATP also restored swelling-activated Cl−currents. The effect of ATP or adenosine was blocked by 8-cyclopentyl-1,3-diproxylxanthine. The ecto-ATPase inhibitor ARL-67156 inhibited the effect of hypotonicity and ATP. Finally, in KO mice, volume-sensitive Cl−currents are potentially functional, but the absence of CFTR precludes their activation by extracellular nucleosides. This observation strengthens the hypothesis that CFTR is a modulator of ATP release in epithelia.

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