Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

Scholl, Ute I.; Abriola, Laura; Zhang, Chengbiao; Reimer, Esther N.; Plummer, Mark S.; Kazmierczak, Barbara I.; Zhang, Junhui; Merkel, Jane S.; Wang, Wenhui; Lifton, Richard P.

doi:10.1172/jci91733

Cited by 64 publications

(58 citation statements)

References 51 publications

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“…A number of somatic mutations have been identified in ion channels and transporters that drive the aldosterone excess in patients with APAs (62,63). No clinical application has been firmly established although a potential future use may lie in steroid profiling to circumvent AVS in patients with bilateral disease by selection of those patients with a high probability of having an APA (64) or by selecting patients with an APA carrying KCNJS mutations using macrolide antibiotics as selective inhibitors (65).…”

Section: Genetic Forms Of Pamentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited

Williams

Reincke

2018

European Journal of Endocrinology

101

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The syndrome of primary aldosteronism (PA) is characterized by hypertension with excessive, autonomous aldosterone production and is usually caused by either a unilateral aldosterone-producing adenoma or bilateral adrenal hyperplasia. The diagnostic workup of PA is a sequence of three phases comprising screening tests, confirmatory tests and the differentiation of unilateral from bilateral forms. The latter step is necessary to determine the optimal treatment approach of unilateral laparoscopic adrenalectomy (for patients with unilateral PA) or medical treatment with a mineralocorticoid receptor antagonist (for patients with bilateral PA). Since the publication of the revised Endocrine Society guideline 2016, a number of key studies have been published. They challenge the recommendations of the guideline in some areas and confirm current practice in others. Herein, we present the recent developments and current approaches to the medical management of PA.

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Section: Genetic Forms Of Pamentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited

Williams

Reincke

2018

European Journal of Endocrinology

101

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“…Even more surprisingly, mutant GIRK4, but not the wild-type channel, is effectively inhibited by a series of molecules belonging to the macrolide class of antibiotics and by synthetic derivatives lacking the antibiotic activity (54). In light of this recent finding, a murine model of PA due to a germline KNCJ5 mutation would be an extremely valuable tool for further pharmacological studies.…”

Section: Page 11 Of 31mentioning

confidence: 99%

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Monticone

Buffolo

Tetti

et al. 2018

European Journal of Endocrinology

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2 AbstractAldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA, and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis has yet to be uncovered.

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“…Functional molecular imaging approaches using the CXCR4 ligand 68Ga-pentixafor may visualise the hypersecreting adrenal [75] as well as other functional imaging methods such as 11 C-metomidate positron emission tomography-CT imaging and (6β-131I) iodomethyl-19-norcholesterol scan [14]. Other approaches include potentially reducing the numbers of patients that undergo AVS by selecting patients with an APA by mass spectrometry-based peripheral venous steroid profiling [76,77] or using macrolide antibiotics that selectively inhibit aldosterone hypersecretion from APAs carrying KCNJ5 mutations [78][79][80]. [40,[81][82][83][84][85]…”

Section: Discussionmentioning

confidence: 99%

Treatment of Unilateral PA by Adrenalectomy: Potential Reasons for Incomplete Biochemical Cure

Yang

Reincke

Williams

2018

Exp Clin Endocrinol Diabetes

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The importance of an early diagnosis and appropriate management of patients with primary aldosteronism (PA) has become increasingly clear because of the adverse impact of the disorder on cardiovascular and cerebrovascular events and target organ damage. Adrenalectomy potentially cures patients with unilateral PA resulting in normalisation of blood pressure or significant clinical improvements in the majority of patients. Different criteria have been used to evaluate outcomes of unilateral adrenalectomy. Clinical remission (cure of hypertension) is observed in 6% to 86% of patients and clinical benefits from surgery are seen in the majority. Several factors have been identified that predict clinical success after surgery such as age, sex, anti-hypertensive medication dosage and known duration of hypertension. Biochemical remission of PA after unilateral adrenalectomy, characterised by the resolution of hyperaldosteronism and correction of pre-surgical hypokalaemia, is observed in 67% to 100% of patients with unilateral PA. In only a small proportion of patients, adrenalectomy fails to resolve hyperaldosteronism and inappropriate aldosterone production persists after surgery. In this review we discuss the potential reasons for failing to cure hyperaldosteronism after unilateral adrenalectomy for unilateral primary aldosteronism.

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Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

Cited by 64 publications

References 51 publications

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited

MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of primary aldosteronism: the Endocrine Society guideline 2016 revisited

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Treatment of Unilateral PA by Adrenalectomy: Potential Reasons for Incomplete Biochemical Cure

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