Angiotensin II exerts glucose-dependent effects on Kvcurrents in mouse pancreatic β-cells via angiotensin II type 2 receptors

Abstract

Hyperglycemia-associated glucotoxicity induces β-cell apoptosis but the underlying mechanisms are unknown. Interestingly, prolonged exposure to high glucose upregulates the expression and function of the renin-angiotensin system (RAS). We hypothesize that the voltage-gated outward potassium (Kv) current, which governs β-cell membrane potential and insulin secretion, has a role in glucotoxicity. In this study, we investigated the effects of prolonged exposure to high glucose on mouse pancreatic β-cells and concurrent effects on the RAS by examining changes in expression of angiotensin II (ANG II) receptors and changes in the expression and activity of Kvchannels. β-Cells were incubated in high glucose medium for 1–7 days and then were examined with electrophysiological and molecular biology techniques. Prolonged exposure to high glucose produced a marked increase in β-cell primary Kvchannel subunit, Kv2.1, expression and Kvcurrent amplitude. Enhanced expression of ANG II type 1 receptor (AT1R) was also observed under high glucose conditions, whereas blockade of AT1R by losartan did not alter Kvchannel expression. External application of ANG II reduced Kvcurrent amplitude under normal, but not high, glucose conditions. The effect of ANG II on Kvchannel gating was abolished by ANG II type 2 receptor (AT2R) antagonism. These data suggest that hyperglycemia alters β-cell function through modification of the Kvchannel which may be associated with the RAS.