Two-pore domain potassium channels and aldosterone secretion

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7. Project Summary / Abstract 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.