Lower Expression of the TWIK-Related Acid-Sensitive K+ Channel 2 (TASK-2) Gene Is a Hallmark of Aldosterone-Producing Adenoma Causing Human Primary Aldosteronism

Lenzini, Livia; Caroccia, Brasilina; Campos, Abril González; Fassina, Ambrogio; Belloni, Anna S.; Seccia, Teresa Maria; Kuppusamy, Maniselvan; Ferraro, Silvia; Skander, Ghizlane; Bäder, Michael; Rainey, William E.; Rossi, Gian Paolo

doi:10.1210/jc.2013-2900

Cited by 50 publications

(44 citation statements)

References 37 publications

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“…Genetic deletion of task1 and/or task3 in mice is associated with a PA phenotype (110,217,226). Lenzini et al (280) analyzed the transcriptome and microRNA profiles of APAs and found lower expression than in normal adrenal cortex of TASK-2 and a higher expression of two microRNAs, hsa-miR-23 and hsa-miR-34, which were found to decrease TASK-2 mRNA expression by binding to its 3'-untranslated region (280). Transfection of adrenocortical H295R cells with a TASK-2 dominant-negative mutant construct significantly increased aldosterone production and gene expression of CYP11B2 and StAR.…”

Section: G Transcriptome Analysesmentioning

confidence: 99%

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

Stowasser

Gordon

2016

Physiological Reviews

125

134

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In the 60 years that have passed since the discovery of the mineralocorticoid hormone aldosterone, much has been learned about its synthesis (both adrenal and extraadrenal), regulation (by renin-angiotensin II, potassium, adrenocorticotrophin, and other factors), and effects (on both epithelial and nonepithelial tissues). Once thought to be rare, primary aldosteronism (PA, in which aldosterone secretion by the adrenal is excessive and autonomous of its principal regulator, angiotensin II) is now known to be the most common specifically treatable and potentially curable form of hypertension, with most patients lacking the clinical feature of hypokalemia, the presence of which was previously considered to be necessary to warrant further efforts towards confirming a diagnosis of PA. This, and the appreciation that aldosterone excess leads to adverse cardiovascular, renal, central nervous, and psychological effects, that are at least partly independent of its effects on blood pressure, have had a profound influence on raising clinical and research interest in PA. Such research on patients with PA has, in turn, furthered knowledge regarding aldosterone synthesis, regulation, and effects. This review summarizes current progress in our understanding of the physiology of aldosterone, and towards defining the causes (including genetic bases), epidemiology, outcomes, and clinical approaches to diagnostic workup (including screening, diagnostic confirmation, and subtype differentiation) and treatment of PA.

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Section: G Transcriptome Analysesmentioning

confidence: 99%

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

Stowasser

Gordon

2016

Physiological Reviews

125

134

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“…For example, alterations in one step could induce a switch activation from one function to another, resulting in the loss or gain of a physiological function, and thus in pathological situations (Lefrançois- Martinez et al 2004, Horvath et al 2006, Tsai & Beavo 2011, de Joussineau et al 2012, Leal et al 2015. The integration of various technologies (such as transcriptomics, proteomics, or metabolomics) combined with computational and mathematical models could be used to identify new therapeutic agents, drug targets, and novel biomarkers, as demonstrated for other paradigms in several recent publications (de Fraipont et al 2005, Choi et al 2011, Patel et al 2013, Lenzini et al 2014, Resendis-Antonio et al 2015.…”

Section: Conclusion: Challenges and Perspectivesmentioning

confidence: 99%

“…TASK channels maintain the membrane potential of ZG cells at a polarized ∼70 mV by being constitutively open and acting as a K + leak channel. Decreased expression of TASK2 is also associated with a higher expression of miR-23 and miR-34, steroidogenic acute regulatory protein, and CYP11B2, thus enhancing aldosterone production (Lenzini et al 2014). Besides TASK channels, mutations occurring near the selectivity filter of the inward rectifying K + channel KCNJ5 (Kir3.4) also result in PA (Choi et al 2011).…”

Section: From Genomics To Physiopathologymentioning

confidence: 99%

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

Gallo‐Payet

2016

Journal of Molecular Endocrinology

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The pituitary adrenocorticotropic hormone (ACTH) plays a pivotal role in homeostasis and stress response and is thus the major component of the hypothalamo–pituitary–adrenal axis. After a brief summary of ACTH production from proopiomelanocortin (POMC) and on ACTH receptor properties, the first part of the review covers the role of ACTH in steroidogenesis and steroid secretion. We highlight the mechanisms explaining the differential acute vs chronic effects of ACTH on aldosterone and glucocorticoid secretion. The second part summarizes the effects of ACTH on adrenal growth, addressing its role as either a mitogenic or a differentiating factor. We then review the mechanisms involved in steroid secretion, from the classical Cyclic adenosine monophosphate second messenger system to various signaling cascades. We also consider how the interaction between the extracellular matrix and the cytoskeleton may trigger activation of signaling platforms potentially stimulating or repressing the steroidogenic potency of ACTH. Finally, we consider the extra-adrenal actions of ACTH, in particular its role in differentiation in a variety of cell types, in addition to its known lipolytic effects on adipocytes. In each section, we endeavor to correlate basic mechanisms of ACTH function with the pathological consequences of ACTH signaling deficiency and of overproduction of ACTH.

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“…Similarly, the low expression of KCNK9, coding for TASK3, in human adrenal cortex is not in favor of a major role of this channel in the development of APA and no somatic mutations have been reported. Recently Lenzini et al (2014) reported reduced expression of TASK2, encoded by KCNK5, in APA compared with normal adrenal cortex. The overexpression of a dominant-negative mutant of TASK2 resulted in an increase in aldosterone production due to increase in CYP11B2 and STAR expression in H295R cells.…”

Section: Familial Hyperaldosteronism Type IImentioning

confidence: 99%

An update on novel mechanisms of primary aldosteronism

Zennaro¹,

Boulkroun²,

Fernandes-Rosa³

2014

Journal of Endocrinology

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Primary aldosteronism (PA) is the most common and curable form of secondary hypertension. It is caused in the majority of cases by either unilateral aldosterone overproduction due to an aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia. Recent advances in genome technology have allowed researchers to unravel part of the genetic abnormalities underlying the development of APA and familial hyperaldosteronism. Recurrent somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and ATPases (ATP1A1 and ATP2B3) regulating intracellular ionic homeostasis and cell membrane potential have been identified in APA. Similar germline mutations of KCNJ5 were identified in a severe familial form of PA, familial hyperaldosteronism type 3 (FH3), whereas de novo germline CACNA1D mutations were found in two cases of hyperaldosteronism associated with a complex neurological disorder. These results have allowed a pathophysiological model of APA development to be established. This model involves modifications in intracellular ionic homeostasis and membrane potential, accounting for w50% of all tumors, associated with specific gender differences and severity of PA. In this review, we describe the different genetic abnormalities associated with PA and discuss the mechanisms whereby they lead to increased aldosterone production and cell proliferation. We also address some of the foreseeable consequences that genetic knowledge may contribute to improve diagnosis and patient care.

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Lower Expression of the TWIK-Related Acid-Sensitive K+ Channel 2 (TASK-2) Gene Is a Hallmark of Aldosterone-Producing Adenoma Causing Human Primary Aldosteronism

Cited by 50 publications

References 37 publications

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

60 YEARS OF POMC: Adrenal and extra-adrenal functions of ACTH

An update on novel mechanisms of primary aldosteronism

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