Molecular Mechanisms of Primary Aldosteronism

Tevosian, Sergei G.; Fox, Shawna C.; Ghayee, Hans K.

doi:10.3803/enm.2019.34.4.355

Cited by 8 publications

(5 citation statements)

References 121 publications

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“…Over the last 10-15 years, knowledge of the genetic basis of PA has allowed the identification of Mendelian forms of PA, which are highly prevalent in children and adolescents ( 6 – 8 ).…”

Section: Aldosterone As a Key Player ( Table 1 ; ...mentioning

confidence: 99%

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Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized?

Costa-Barbosa¹,

Giorgi

Kater³

2022

Archives of Endocrinology and Metabolism

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High blood pressure (BP) is not restricted to adults; children and adolescents may also be affected, albeit less frequently. Aside from unfavorable environmental factors, such as obesity and sedentary life leading to early-onset essential hypertension (HT), several secondary causes must be investigated in the occasional hypertensive child/adolescent. Endocrine causes are relevant and multiple, related to the pituitary, thyroid, parathyroid, gonads, insulin, and others, but generally are associated with adrenal disease. This common scenario has several vital components, such as aldosterone, deoxycorticosterone (DOC), cortisol, or catecholamines, but there are also monogenic disorders involving the kidney tubule that cause inappropriate salt retention and HT that simulate adrenal disease. Finally, a blood vessel disease was recently described that may also participate in this vast spectrum of pediatric hypertensive disease. This review will shed some light on the diagnosis and management of conditions, focusing on the most prevalent adrenal (or adrenal-like) disturbances causing HT.

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Section: Aldosterone As a Key Player ( Table 1 ; ...mentioning

confidence: 99%

“…The remaining 5%-10% are familial forms with autosomal dominant inheritance, predominantly affecting young people. Over the last 10-15 years, knowledge of the genetic basis of PA has allowed the identification of Mendelian forms of PA, which are highly prevalent in children and adolescents (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized?

Costa-Barbosa¹,

Giorgi

Kater³

2022

Archives of Endocrinology and Metabolism

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“…Numerous studies have now been performed examining tissue from surgically resected APAs to identify mutations characteristic of various disorders, including PA. Gain-of-function mutations in different genes, coding for cation channels ( KCNJ5 , CACNA1D , CACNA1H ) and ATPases ( ATP1A1 and ATP2B3 ), regulating intracellular ion homeostasis, and plasma membrane potential have been described in in nearly 88% of sporadic APAs [ 43 ]. The most commonly identified mutations are KCNJ5 (43%), CACNA1D (21%), and ATP1A1 (17%) ( Table 3 ) [ 30 ].…”

Section: Genetic Basis Of Pamentioning

confidence: 99%

Progress on Genetic Basis of Primary Aldosteronism

et al. 2021

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Primary aldosteronism (PA) is a heterogeneous group of disorders caused by the autonomous overproduction of aldosterone with simultaneous suppression of plasma renin activity (PRA). It is considered to be the most common endocrine cause of secondary arterial hypertension (HT) and is associated with a high rate of cardiovascular complications. PA is most often caused by a bilateral adrenal hyperplasia (BAH) or aldosterone-producing adenoma (APA); rarer causes of PA include genetic disorders of steroidogenesis (familial hyperaldosteronism (FA) type I, II, III and IV), aldosterone-producing adrenocortical carcinoma, and ectopic aldosterone-producing tumors. Over the last few years, significant progress has been made towards understanding the genetic basis of PA, classifying it as a channelopathy. Recently, a growing body of clinical evidence suggests that mutations in ion channels appear to be the major cause of aldosterone-producing adenomas, and several mutations within the ion channel encoding genes have been identified. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D) have been identified in nearly 60% of the sporadic APAs, while germline mutations in KCNJ5 and CACNA1H have been reported in different subtypes of familial hyperaldosteronism. These new insights into the molecular mechanisms underlying PA may be associated with potential implications for diagnosis and therapy.

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“…The two subtypes drastically differ also in terms of preferential treatment, being the surgical removal of the adenoma the preferential choice for APA while the pharmacological intervention with Mineralcorticoid Receptor Antagonists (MRAs) is the usual option for BPA. The molecular mechanisms of PA have been partially uncovered in recent years, but much work is still needed to improve our understanding of the intrinsic and extrinsic pathways, especially related to the lack of response to BP-lowering drugs ( 2 ). Overall, the current work-up for the diagnosis of PA is cumbersome, time-consuming, relatively expensive, and it requires specific technical skills or experience, thus limiting its potential routine application on the multitude of the hypertensive population.…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of urinary extracellular vesicles highlights specific signatures for patients with primary aldosteronism

et al. 2023

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BackgroundUrinary extracellular vesicles (uEVs) can be released by different cell types facing the urogenital tract and are involved in cellular trafficking, differentiation and survival. UEVs can be easily detected in urine and provide pathophysiological information “in vivo” without the need of a biopsy. Based on these premises, we hypothesized that uEVs proteomic profile may serve as a valuable tool in the differential characterization between Essential Hypertension (EH) and primary aldosteronism (PA).MethodsPatients with essential hypertension (EH) and PA were enrolled in the study (EH= 12, PA=24: 11 Bilateral Primary Aldosteronism subtype (BPA) and 13 Aldosterone Producing Adenoma (APA)). Clinical and biochemical parameters were available for all the subjects. UEVs were isolated from urine by ultracentrifugation and analysed by Transmission Electron Microscopy (TEM) and nanotrack particle analysis (NTA). UEVs protein content was investigated through an untargeted MS-based approach. Statistical and network analysis was performed to identify potential candidates for the identification and classification of PA.ResultsMS analysis provided more than 300 protein identifications. Exosomal markers CD9 and CD63 were detected in all samples. Several molecules characterizing EH vs PA patients as well as BPA and APA subtypes were identified after statistical elaboration and filtering of the results. In particular, some key proteins involved in water reabsorption mechanisms, such as AQP1 and AQP2, were among the best candidates for discriminating EH vs PA, as well as A1AG1 (AGP1).ConclusionThrough this proteomic approach, we identified uEVs molecular indicators that can improve PA characterization and help in the gain of insights of the pathophysiological features of this disease. In particular, PA was characterized by a reduction of AQP1 and AQP2 expression as compared with EH.

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Molecular Mechanisms of Primary Aldosteronism

Cited by 8 publications

References 121 publications

Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized?

Focus on adrenal and related causes of hypertension in childhood and adolescence: Rare or rarely recognized?

Progress on Genetic Basis of Primary Aldosteronism

Proteomic analysis of urinary extracellular vesicles highlights specific signatures for patients with primary aldosteronism

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