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

1 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; 2 Prince Henry's Institute of Medical Research, Melbourne, Victoria, Australia; and 3 School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia Submitted 5 November 2008 ; accepted in final form 29 October 2009 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 (K v ) 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 K v channels. 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 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 β-cell function through modification of the K v channel which may be associated with the RAS. renin-angiotensin system; electrophysiology; K v 2.1 channel; losartan; PD123319; insulin secretion Address for reprint requests and other correspondence: P. S. Leung, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong (e-mail: psleung{at}cuhk.edu.hk ).