Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C105

Oral Communications

Role of mineralocorticoid receptors in mediating endothelial dysfunction in experimental diabetes

K. Lyngsø1, H. Dimke1, P. Lærkegaard Hansen1,2

1. Dept. of Cardiovascular and Renal Research, University of Southern Denmark, Odense C, Denmark. 2. Cardiovascular & Metabolic Disease Innovative Medicines, AstraZeneca, Gothenburg, Sweden.

Introduction: Elevations in circulating levels of aldosterone correlates with increased cardiovascular deaths in diabetic patients. Endothelial dysfunction is a key player in the development of vascular complications seen in diabetic patients. Increased levels of aldosterone and activation of the mineralocorticoid receptor are associated with endothelial dysfunction and antagonism of the mineralocorticoid receptor is suggested to improve endothelial function. The mineralocorticoid receptor in the endothelium (ECMR) has been found to be harmful in pathophysiological conditions. Hypothesis: We hypothesize, that the detrimental vascular effect of aldosterone in diabetic vascular complications occurs through the mineralocorticoid receptor in the endothelium. Methods: Transgenic mice (MRflox/flox;Tie2-Cre) with a specific deletion of the MR in endothelium and their wildtype littermates (MRflox/flox) were given streptozotozin (STZ) for five consecutive days (55mg/kg/day) to induce diabetes or vehicle. Diabetic mice were re-injected with STZ (single bolus) six weeks after initial injection to maintain diabetes. A 10 % sucrose solution was given during the five injection days to avoid hypoglycemia. Bodyweight and blood glucose levels were measured weekly. After 10 weeks, mesenteric second order resistance arteries were isolated and perfused and both constriction and dilation was assessed in presence of aldosterone and an MR antagonist. Results: STZ injections significantly increased blood glucose levels compared to vehicle controls in both ECMR-KO (18.11±1.11mM vs 6.42±0.12mM) and WT (19.24±1.06mM vs 6.50±0.20mM) with no difference between sexes. There were no difference in weight gain between STZ and VEH. Preliminary data suggests that STZ-treatment only affects dilatation in WT animals where maximal dilatation to acetylcholine was decreased compared to controls (WT: 10.13±4.109% vs. 32.75±6.540% and KO: 37.39±0.3814 vs. 27.19±2.481%, n=3-4, mean±SEM). After incubation with aldosterone (10-9M, one hour), dilatation was further decreased in WT (7.219±5.167% and 20.31±1.682, n=3-4, mean±SEM), but not in KO (36.59±2.554% and 29.66±4.992%, n=3-4, mean±SEM) no matter of STZ-treatment or vehicle. Incubation with the MR antagonist spironolactone (10-7M, 30min) improved maximal dilatation in both STZ-treated WT and KO (15.87±6.49% and 41.84±5.35%, n=3, mean±SEM). Conclusion: These data suggests that the endothelial cell specific mineralocorticoid receptor is involved in decreasing dilatation to acetylcholine in STZ-treated mice, but more mice needs to be included before solid conclusions can be made.

Where applicable, experiments conform with Society ethical requirements