Role of Kv7 channels in renin-angiotensin system (RAS)-induced disruption of the blood-brain barrier

Blood-brain barrier (BBB) disruption and the consequent alteration of solute and ion transport play a pivotal role in the onset and progression of many neurological diseases, including epilepsy. Among the players that have been shown to modulate BBB function, our group recently demonstrated that Kv7 channels, a family of voltage-gated potassium channels, are critical modulators of barrier permeability, both in physiological conditions and experimental models of seizures. Accumulating evidence suggest that the renin-angiotensin system (RAS) is altered during epilepsy and affects BBB permeability; moreover, RAS modulate the expression and function of several classes of ion channels including members of the Kv7 family. In this study, we evaluated the involvement of endothelial Kv7 channels in the alteration of BBB permeability prompted by Angiotensin II (Ang II) exposure. Immunofluorescence experiments in clonal endothelial cells (ECs) (BEND-3) revealed that Ang II (100 nM, 6-24 hours) reduced the plasma-membrane expression of Kv7.5 as well as of a tight junction-specific marker (Zonula Occludens-1, ZO-1), thereby decreasing Tight Junction Organization Rate, indicating disrupted ECs integrity. Similar changes in Kv7.5 and ZO-1 expression were also observed in Western blot experiments. Incubation of BEND-3 and primary ECs with Ang II reduced Trans-Endothelial Electrical Resistance; these effects were prevented by the selective Kv7 activator retigabine (10 μM). Overall, these results suggest that the downregulation of endothelial Kv7 channels might be involved in the pathological changes of BBB caused by Ang II and that their pharmacological activation could be a useful strategy to prevent BBB disruption prompted by overactive RAS.