title: TASK-3 channel deletion in mice recapitulates low-renin essential hypertension.
abstract: Idiopathic primary hyperaldosteronism (IHA) and low-renin essential hypertension (LREH) are common forms of hypertension, characterized by an elevated aldosterone-renin ratio and hypersensitivity to angiotensin II. They are suggested to be 2 states within a disease spectrum that progresses from LREH to IHA as the control of aldosterone production by the renin-angiotensin system is weakened. The mechanism(s) that drives this progression remains unknown. Deletion of Twik-related acid-sensitive K(+) channels (TASK) subunits, TASK-1 and TASK-3, in mice (T1T3KO) produces a model of human IHA. Here, we determine the effect of deleting only TASK-3 (T3KO) on the control of aldosterone production and blood pressure. We find that T3KO mice recapitulate key characteristics of human LREH, salt-sensitive hypertension, mild overproduction of aldosterone, decreased plasma-renin concentration with elevated aldosterone:renin ratio, hypersensitivity to endogenous and exogenous angiotensin II, and failure to suppress aldosterone production with dietary sodium loading. The relative differences in levels of aldosterone output and aldosterone:renin ratio and in autonomy of aldosterone production between T1T3KO and T3KO mice are reminiscent of differences in human hypertensive patients with LREH and IHA. Our studies establish a model of LREH and suggest that loss of TASK channel activity may be one mechanism that advances the syndrome of low renin hypertension.
authors.affiliation: Department of Pharmacology, University of Virginia, School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Nick A
authors.initials: NA
authors.lastname: Guagliardo
authors.forename: Junlan
authors.initials: J
authors.lastname: Yao
authors.forename: Changlong
authors.initials: C
authors.lastname: Hu
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Schertz
authors.forename: David A
authors.initials: DA
authors.lastname: Tyson
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
authors.forename: Paula Q
authors.initials: PQ
authors.lastname: Barrett
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D006929:Hyperaldosteronism / Q000235:genetics* / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D012084:Renin-Angiotensin System / Q000235:genetics* / Q000502:physiology; D012680:Sensitivity and Specificity; D017384:Sequence Deletion; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology
chemical_list: D015221:Potassium Channels; C511784:TASK3 protein, mouse; D000804:Angiotensin II; D000450:Aldosterone; D012964:Sodium