Abstract MP09: Adrenal-specific Deletion of TASK Channels Evokes Normal-Renin Hypertension
Objectives: Dysregulation of aldosterone (Aldo) production is predicted to evoke major features of idiopathic primary hyperaldosteronism (IHA): low renin, elevated blood pressure and suppressed control by high Na. We have previously demonstrated in mice that global deletion of background TWIK-related acid-sensitive K (TASK) channels (TASK-1, TASK-3) effect a ~20mV decrease in the membrane potential of Zona Glomerulosa (ZG) cells to produce frank autonomous overproduction of Aldo, low renin, and hypertension (HT), mimicking the salient features of human IHA. In the current study, we ask if specific deletion of TASK channels in ZG cells is sufficient to produce hyperaldosteronism and the predicted sequela or if extra-adrenal deletion of TASK channels is required.
Design and Methods: We generated a trigenic mouse-line (AS+Cre::TASK-1ff::TASK-3ff, zT1T3KO) in which TASK-1 and TASK-3 subunits were specifically deleted in ZG cells. The renin-angiotensin-aldosterone system (RAAS) was evaluated in mice housed in metabolic cages and stabilized on various salt diets. Urinary Aldo concentration was measured and normalized to creatinine (ng Aldo/mg creatinine; 24 hr. urine collection). Blood pressure was recorded in conscious, freely moving mice using radio telemetry, and plasma renin concentration was measured from tail vein sampling.
Results: Overproduction of aldosterone on normal-salt diet (0.3% Na) was modest in zT1T3KO mice compared to littermate controls (WT; WT 9.4; KO 11.8 ng/mg, 1.25-fold). Suppression of Aldo production by high-salt (2% Na) was blunted, exaggerating the difference in Aldo production between genotypes (WT 3.0; KO 7.4 ng/mg, 2.43-fold). zT1T3KO mice were hypertensive (mean MAP: WT 103.5; KO 113.1 mmHg), yet renin levels remained normal. Neither hyperaldosteronism nor HT could be corrected by angiotensin II receptor blockade, suggesting overproduction of Aldo and HT are independent of RAAS.
Conclusions: Limiting TASK deletion to ZG cells results in normal renin HT driven by modest autonomous hyperaldosteronism, a stark contrast to the phenotypic features of IHA recapitulated by global TASK deletion. Together these mouse models provide insight into the role of ZG- vs extra-adrenal-dysfunction in the pathology of IHA.
Author Disclosures: N.A. Guagliardo: None. T.H. Le: None. D.A. Bayliss: None. D.T. Breault: None. P.Q. Barrett: None.
- © 2015 by American Heart Association, Inc.