Low-renin hypertension (LREH) and idiopathic primary hyperaldosteronism (IHA) occur commonly, and predispose to the development of cardiovascular and renal disease. Within the disease spectrum of low renin hypertension (LRH), hyperaldosteronism ranges from mild to marked, but it always remains inappropriate for the level of plasma renin. The primary causes for LRH remain ill-defined. Here, we propose that excess aldosterone production may not be the sole causative factor contributing to low-renin hypertension in LREH or IHA. Our general hypothesis is that the low renin-hypertensive state in LRH is a consequence of an increased sensitivity to Angiotensin II (Ang II) manifest at multiple sites: the adrenal gland (hyperaldosteronism) the vasculature (hypertension) and/or the juxtaglomerular apparatus (feed-back inhibition of renin secretion, low- renin). We previously demonstrated that global disruption of genes encoding TASK two-pore domain potassium channels produces cardinal features of LREH and IHA (low renin hypertension with high aldosterone:renin ratios, hypersensitivity to Ang II and variable degrees of autonomous aldosterone production). Therefore, we further hypothesize that disrupting TASK channel activity, as well as the removal of TASK protein itself, is required to produce hyper-reactivity to Ang II. To provide human disease relevance to our proposed work, we use genomics to test for novel associations of human TASK channel gene variants with measures of hypertension, aldosterone, renin activity and ARR in MESA (Multi-Ethnic Study of Atherosclerosis) We propose to use a combination of molecular/cell biological and electrophysiological recording techniques, along with genomic approaches, to test our hypotheses in two Specific Aims.
In Aim 1, we generate and validate new mouse models in which TASK channels are deleted specifically in aldosterone producing zona glomerulosa cells (ZG) and in which TASK KO ZG cells are marked by green fluorescent protein. We use these unique mouse models of LRH to determine which phenotypic features of LRH are produced by hyperaldosteronism, per se. We use these findings to inform a genetic analysis in humans.
In Aim 2, we determine the cellular basis for hypersensitivity to Ang II testing contributions of: i) TASK channel activity;ii) AT1 receptor activity-state;iii) cellular electrical excitability;and iv) altered Ca channel activity. Our 2+ proposed studies will provide new information about the cell biology of ZG cells, the cellular mechanisms that underlie exaggerated responses in LRH, and the contribution of genetic differences in TASK channels to human hypertension. If our hypotheses are correct, they also will provide a rational basis for development or evaluation of new medical treatments for LRH, for which there remains a high prevalence of resistance to currently available therapies.

Public Health Relevance

Low renin hypertension (LRH) is a spectrum of diseases that is accompanied by greater cardiovascular and renal damage than other forms of hypertension. The underlying causes for this type of hypertension remain unknown. We have developed mouse models that reproduce key features of this syndrome. We use these mouse models to understand the causes of LRH, and to inform studies in which we look for changes in human genes that could explain this type of hypertension. Our goal is to improve both our understanding of the pathological mechanisms underlying these disorders and our ability to find potential new therapies.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Hypertension and Microcirculation Study Section (HM)
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Maric-Bilkan, Christine
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University of Virginia
Schools of Medicine
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Guagliardo, Nick A; Yao, Junlan; Stipes, Eric J et al. (2018) Adrenal Tissue-Specific Deletion of TASK Channels Causes Aldosterone-Driven Angiotensin II-Independent Hypertension. Hypertension :HYPERTENSIONAHA11811962
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
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
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
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

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