Abstract
Overt dysregulation of the renin-angiotensin-aldosterone system (primary aldosteronism: APA and IHA) has long been known for its deleterious cardiovascular consequences. Recently, however, subclinical mild hyperaldosteronism was recognized as a significant risk factor for hypertension, and may represent an early stage in the disease spectrum. Previously, we developed mouse models of hyperaldosteronism by globally deleting subunits of the TWIK-related acid sensitive potassium channel (TASK). Global TASK-1 (Kcnk3) and TASK-3 (Kcnk9) KO mice markedly overproduce Ang II-independent (autonomous) aldosterone, that is not suppressed by high dietary sodium and is accompanied by low renin and elevated blood pressure. Here, we report a novel mouse model of mild hyperaldosteronism produced by the zona glomerulosa (zG)-specific deletion of TASK channels. To generate trigenic Cyp11b2Cre/+ :: Kcnk3f/f :: Kcnk9f/f mice (zG-TASK-KO), the Cyp11b2Cre/+ strain that expresses Cre-recombinase under the aldosterone synthase promoter was crossed with the Kcnk3f/f :: Kcnk9f/f strain. We confirmed restriction of Cre-expression to the zG layer by qRT-PCR and immunohistochemistry using a Cre-dependent reporter mouse (Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/J ). Despite normal plasma renin, zG-TASK-KO mice displayed a mild increase in 24-hr. urinary aldosterone excretion (11.8±0.8 KO vs 9.3±0.6 controls; ng/mg-aldosterone/creatinine, p<0.05) that was much less than the frank increase observed in global TASK-KO mice (42.6±6.9 ng/mg, aldosterone/creatinine, p<0.05). Hyperaldosteronism of zG-TASK-KO mice failed to normalize with AT1R antagonism (candesartan) or salt suppression (4% Na-diet). Twenty-four-hour blood pressure of conscious, freely behaving zG-TASK-KO mice was increased compared to control mice (systolic: 133.3±1.8 mmHg KO vs 122.7±1.2 mmHg controls, p<0.05) and failed to normalize with candesartan, but corrected with MR antagonism (spironolactone). This study demonstrates that a zG-specific channel defect can produce mild autonomous hyperaldosteronism sufficient to cause chronic aldosterone-driven and Angiotensin II-independent blood pressure elevation.
