Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

TASK1 (KCNK3) and TASK3 (KCNK9) are two-pore domain potassium channels highly expressed in adrenal glands. TASK1/TASK3 heterodimers are believed to contribute to the background conductance whose inhibition by angiotensin II stimulates aldosterone secretion. We used task1-/- mice to analyze the role of this channel in adrenal gland function. Task1-/- exhibited severe hyperaldosteronism independent of salt intake, hypokalemia, and arterial 'low-renin' hypertension. The hyperaldosteronism was fully remediable by glucocorticoids. The aldosterone phenotype was caused by an adrenocortical zonation defect. Aldosterone synthase was absent in the outer cortex normally corresponding to the zona glomerulosa, but abundant in the reticulo-fasciculata zone. The impaired mineralocorticoid homeostasis and zonation were independent of the sex in young mice, but were restricted to females in adults. Patch-clamp experiments on adrenal cells suggest that task3 and other K+ channels compensate for the task1 absence. Adrenal zonation appears as a dynamic process that even can take place in adulthood. The striking changes in the adrenocortical architecture in task1-/- mice are the first demonstration of the causative role of a potassium channel in development/differentiation.
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PMID:Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. 1803 54

When inappropriate for salt status, the mineralocorticoid aldosterone induces cardiac and renal injury. Autonomous overproduction of aldosterone from the adrenal zona glomerulosa (ZG) is also the most frequent cause of secondary hypertension. Yet, the etiology of nontumorigenic primary hyperaldosteronism caused by bilateral idiopathic hyperaldosteronism remains unknown. Here, we show that genetic deletion of TWIK-related acid-sensitive K (TASK)-1 and TASK-3 channels removes an important background K current that results in a marked depolarization of ZG cell membrane potential. Although TASK channel deletion mice (TASK-/-) adjust urinary Na excretion and aldosterone production to match Na intake, they produce more aldosterone than control mice across the range of Na intake. Overproduction of aldosterone is not the result of enhanced activity of the renin-angiotensin system because circulating renin concentrations remain either unchanged or lower than those of control mice at each level of Na intake. In addition, TASK-/- mice fail to suppress aldosterone production in response to dietary Na loading. Autonomous aldosterone production is also demonstrated by the failure of an angiotensin type 1 receptor blocker, candesartan, to normalize aldosterone production to control levels in TASK-/- mice. Thus, TASK-/- channel knockout mice exhibit the hallmarks of primary hyperaldosteronism. Our studies establish an animal model of nontumorigenic primary hyperaldosteronism and identify TASK channels as a possible therapeutic target for primary hyperaldosteronism.
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PMID:TASK channel deletion in mice causes primary hyperaldosteronism. 1825 Mar 25

Idiopathic primary hyperaldosteronism (IHA) and low-renin essential hypertension (LREH) are common forms of hypertension, characterized by an elevated aldosterone-renin ratio and hypersensitivity to angiotensin II. They are suggested to be 2 states within a disease spectrum that progresses from LREH to IHA as the control of aldosterone production by the renin-angiotensin system is weakened. The mechanism(s) that drives this progression remains unknown. Deletion of Twik-related acid-sensitive K(+) channels (TASK) subunits, TASK-1 and TASK-3, in mice (T1T3KO) produces a model of human IHA. Here, we determine the effect of deleting only TASK-3 (T3KO) on the control of aldosterone production and blood pressure. We find that T3KO mice recapitulate key characteristics of human LREH, salt-sensitive hypertension, mild overproduction of aldosterone, decreased plasma-renin concentration with elevated aldosterone:renin ratio, hypersensitivity to endogenous and exogenous angiotensin II, and failure to suppress aldosterone production with dietary sodium loading. The relative differences in levels of aldosterone output and aldosterone:renin ratio and in autonomy of aldosterone production between T1T3KO and T3KO mice are reminiscent of differences in human hypertensive patients with LREH and IHA. Our studies establish a model of LREH and suggest that loss of TASK channel activity may be one mechanism that advances the syndrome of low renin hypertension.
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PMID:TASK-3 channel deletion in mice recapitulates low-renin essential hypertension. 2249 79

The renin-angiotensin system tightly controls aldosterone synthesis. Dysregulation is evident in hypertension (primary aldosteronism), low renin, and resistant hypertension) but also can exist in normotension. Whether chronic, mild aldosterone autonomy can elicit hypertension remains untested. Previously, we reported that global genetic deletion of 2 pore-domain TWIK-relative acid-sensitive potassium channels, TASK-1 and TASK-3, from mice produces striking aldosterone excess, low renin, and hypertension. Here, we deleted TASK-1 and TASK-3 channels selectively from zona glomerulosa cells and generated a model of mild aldosterone autonomy with attendant hypertension that is aldosterone-driven and Ang II (angiotensin II)-independent. This study shows that a zona glomerulosa-specific channel defect can produce mild autonomous hyperaldosteronism sufficient to cause chronic blood pressure elevation.
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PMID:Adrenal Tissue-Specific Deletion of TASK Channels Causes Aldosterone-Driven Angiotensin II-Independent Hypertension. 3058 Jun 87