CFTR mediates cadmium-induced apoptosis through modulation of ROS level in mouse proximal tubule cells

The aim of this study was to characterize the role of CFTR during Cd2+-induced apoptosis. For this purpose primary cultures and cell lines originated from proximal tubules (PCT) of wild-type cftr+/+ and cftr−/− mice were used. In cftr+/+ cells, the application of Cd2+ (5 μM) stimulated within 8 min an ERK1/2-activated CFTR-like Cl− conductance sensitive to CFTRinh-172. Thereafter Cd2+ induced an apoptotic volume decrease (AVD) within 6 h followed by caspase-3 activation and apoptosis. The early increase in CFTR conductance was followed by the activation of volume-sensitive outwardly rectifying (VSOR) Cl− and TASK2 K+ conductances. By contrast, cftr−/− cells exposed to Cd2+ were unable to develop VSOR currents, caspase-3 activity, and AVD process and underwent necrosis. Moreover in cftr+/+ cells, Cd2+ enhanced reactive oxygen species (ROS) production and induced a 50% decrease in total glutathione content (major ROS scavenger in PCT). ROS generation and glutathione decrease depended on the presence of CFTR, since they did not occur in the presence of CFTRinh-172 or in cftr−/− cells. Additionally, Cd2+ exposure accelerates effluxes of fluorescent glutathione S-conjugate in cftr+/+ cells. Our data suggest that CFTR could modulate ROS levels to ensure apoptosis during Cd2+ exposure by modulating the intracellular content of glutathione.