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

Chu KY, Cheng Q, Chen C, Au LS, Seto SW, Tuo Y, Motin L, Kwan YW, Leung PS. Angiotensin II exerts glucose-dependent effects on K-v currents in mouse pancreatic beta-cells via angiotensin II type 2 receptors. Am J Physiol Cell Physiol 298: C313-C323, 2010. First published November 4, 2009; doi: 10.1152/ajpcell.00575.2008.-Hyper-glycemia-associated glucotoxicity induces beta-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 (K-v) current, which governs beta-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 beta-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 K-v channels. beta-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 beta-cell primary K-v channel subunit, K(v)2.1, expression and K-v current amplitude. Enhanced expression of ANG II type 1 receptor (AT(1)R) was also observed under high glucose conditions, whereas blockade of AT(1)R by losartan did not alter K-v channel expression. External application of ANG II reduced K-v current amplitude under normal, but not high, glucose conditions. The effect of ANG II on K-v channel gating was abolished by ANG II type 2 receptor (AT(2)R) antagonism. These data suggest that hyperglycemia alters beta-cell function through modification of the K-v channel which may be associated with the RAS.