Aldosterone is an early-onset pathogenic stimulus that adversely influences cardiovascular and renal homeostasis. It is elevated in heart failure, chronic kidney disease and some forms of hypertension. Although the production of aldosterone in vivo has long been known to be regulated by Ang I and potassium, the contribution of K channel regulation to the physiological actions of Ang II, though hypothesized, has remained unproven. The recent generation of TASK-1, TASK-3, and TASK-1/TASK-3 knockout mice offers the exciting possibility to establish the functional importance of TASK channel regulation to the physiological control of aldosterone production in vivo. Our hypothesis that TASK subunits contribute to background K currents and the control of membrane potential by Ang II and acidification in the aldosterone secreting adrenal zona glomerulosa (ZG) cells is tested in vitro. Moreover, the hypothesis that these channels are important in the regulation of aldosterone production and salt/water balance in vivo is determined under basal conditions and during hormonal and metabolic challenge (i.e., AngII infusion, Na loading and deprivation). We pursue the following specific aims:
Aim 1 : Generate and validate novel conventional and conditional TASK channel subunit knockout mouse lines using qRT-PCR, in situ hybridization, and immunohistochemistry;
Aim 2 : Determine membrane properties of ZG cells in control and TASK channel knockout mice, characterizing background K channel currents and their modulation by AngII, extracellular K and bath pH, and evaluating the role of these channels in setting membrane voltage and supporting ZG cell excitability;
Aim 3 : Evaluate the importance of TASK channel expression to the control of aldosterone production in vivo in control and TASK channel knockout mice determining: the steady-state aldosterone secretory response to RAAS suppression caused by dietary manipulation of salt balance, and the aldosterone secretory response to the delivery of exogenous AngII or acid loading in vivo. The strength of this proposal lies in the combined use of molecular and cell biology, electrophysiology and whole animal experimentation. Minimally, our efforts will clarify the role of TASK channels in the production of aldosterone. Optimally, our work will identify a new target for the therapy of patients with heart failure, chronic kidney disease and resistant hypertension. Project Narrative: Idiopathic primary hyperaldosteronism (IHA) is present in 13% of non-selected hypertensive patients and rises to 20% among those that have resistant hypertension. Using a combination of cellular and in vivo approaches our studies identify TASK K channels as critical membrane proteins that control the production of aldosterone, the steroid hormone that is elevated in IHA. The identification of this target can be used to generate a useful therapy for patients with IHA but also for patients with heart failure and chronic kidney disease where elevated aldosterone also hastens disease progression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL089717-03
Application #
7806371
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Thrasher, Terry N
Project Start
2008-04-03
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
3
Fiscal Year
2010
Total Cost
$404,970
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Yao, Junlan; McHedlishvili, David; McIntire, William E et al. (2017) Functional TASK-3-Like Channels in Mitochondria of Aldosterone-Producing Zona Glomerulosa Cells. Hypertension 70:347-356
Barrett, Paula Q; Guagliardo, Nick A; Klein, Peter M et al. (2016) Role of voltage-gated calcium channels in the regulation of aldosterone production from zona glomerulosa cells of the adrenal cortex. J Physiol 594:5851-5860
Yang, Tingting; Zhang, Hai-Liang; Liang, Qingnan et al. (2016) Small-Conductance Ca2+-Activated Potassium Channels Negatively Regulate Aldosterone Secretion in Human Adrenocortical Cells. Hypertension 68:785-95
Manichaikul, Ani; Rich, Stephen S; Allison, Matthew A et al. (2016) KCNK3 Variants Are Associated With Hyperaldosteronism and Hypertension. Hypertension 68:356-64
Freedman, Bethany D; Kempna, Petra Bukovac; Carlone, Diana L et al. (2013) Adrenocortical zonation results from lineage conversion of differentiated zona glomerulosa cells. Dev Cell 26:666-673
Hu, Changlong; Rusin, Craig G; Tan, Zhiyong et al. (2012) Zona glomerulosa cells of the mouse adrenal cortex are intrinsic electrical oscillators. J Clin Invest 122:2046-53
Jung, Jeesun; Barrett, Paula Q; Eckert, George J et al. (2012) Variations in the potassium channel genes KCNK3 and KCNK9 in relation to blood pressure and aldosterone production: an exploratory study. J Clin Endocrinol Metab 97:E2160-7
Guagliardo, Nick A; Yao, Junlan; Hu, Changlong et al. (2012) TASK-3 channel deletion in mice recapitulates low-renin essential hypertension. Hypertension 59:999-1005
Guagliardo, Nick A; Yao, Junlan; Hu, Changlong et al. (2012) Minireview: aldosterone biosynthesis: electrically gated for our protection. Endocrinology 153:3579-86
Guagliardo, Nick A; Yao, Junlan; Bayliss, Douglas A et al. (2011) TASK channels are not required to mount an aldosterone secretory response to metabolic acidosis in mice. Mol Cell Endocrinol 336:47-52

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