Retinoic acid receptor α as a novel contributor to adrenal cortex structure and function through interactions with Wnt and Vegfa signalling

International audiencePrimary aldosteronism (PA) is the most frequent form of secondary arterial hypertension. Mutations in different genes increase aldosterone production in PA, but additional mechanisms may contribute to increased cell proliferation and aldosterone producing adenoma (APA) development. We performed transcriptome analysis in APA and identified retinoic acid receptor alpha (RARα) signaling as a central molecular network involved in nodule formation. To understand how RARα modulates adrenal structure and function, we explored the adrenal phenotype of male and female Rarα knockout mice. inactivation of Rarα in mice led to significant structural disorganization of the adrenal cortex in both sexes, with increased adrenal cortex size in female mice and increased cell proliferation in males. Abnormalities of vessel architecture and extracellular matrix were due to decreased Vegfa expression and modifications in extracellular matrix components. On the molecular level, Rarα inactivation leads to inhibition of non-canonical Wnt signaling, without affecting the canonical Wnt pathway nor PKA signaling. Our study suggests that Rarα contributes to the maintenance of normal adrenal cortex structure and cell proliferation, by modulating Wnt signaling. Dysregulation of this interaction may contribute to abnormal cell proliferation, creating a propitious environment for the emergence of specific driver mutations in PA. Primary aldosteronism (PA) is the most common and curable form of secondary arterial hypertension, with prevalence estimations of up to 10% of cases in referred hypertensive patients, 4% of patients in primary care 1,2 and 20% of patients with resistant hypertension 3,4. Rapid diagnosis and treatment are important to prevent severe cardiovas-cular consequences of long term aldosterone exposure, which are independent of blood pressure levels and are du

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production

Caractérisation de protéines régulées précocement par l'aldostérone et la vasopressine dans le tubule collecteur rénal

Deux composés benzéniques poly-substitués par des groupes pyrroliques, le 1,3,5-tripyrrolylbenzène et l'hexapyrrolylbenzène, ont étés utilisés comme réactifs de synthèse de semi-conducteurs organique p-conjugué. Le couplage des groupes pyrroliques du 1,3,5-tripyrrolylbenzène est intermoléculaire et conduit à la formation d'un polymère organique p-conjugué tandis qu'il est pour l'hexapyrrolylbenzène intramoléculaire de type radical-cation substrat et conduit à la formation de molécules discoïdes qui s'assemblent en matériau organique conducteur p-empilé. Notre approche a permis de dégager des critères structuraux pour les molécules réactives permettant de contrôler la nature (polymère-p ou matériau p-empilé) du semi-conducteur organique produit.PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Overview of aldosterone-related genetic syndromes and recent advances

International audiencePurpose of review: Primary aldosteronism is the most common form of secondary hypertension. Early diagnosis and treatment are key to cure of hypertension and prevention of cardiovascular complications. Recent genetic discoveries have improved our understanding on the pathophysiology of aldosterone production and triggered the development of new diagnostic procedures and targeted treatments for PA. Recent findings: Different inherited genetic abnormalities distinguish specific forms of familial hyperaldosteronism. Somatic mutations are found not only in aldosterone producing adenoma leading to primary aldosteronism, but also in aldosterone producing cell clusters of normal and micronodules from image-negative adrenal glands. Genetic knowledge has allowed the discovery of surrogate biomarkers and specific pharmacological inhibitors. Aging appears to be associated with dysregulated and relatively autonomous aldosterone production. Summary: New biochemical markers and pharmacological approaches may allow pre-operative identification of somatic mutation carriers and use of targeted treatments

Progrès récents dans la génétique de l’hyperaldostéronisme primaire

L’hyperaldostéronisme primaire est la forme la plus fréquente d’hypertension artérielle secondaire. Les principales causes en sont les adénomes produisant de l’aldostérone et les hyperplasies bilatérales des surrénales. Des avancées technologiques récentes ont permis d’identifier certaines des anomalies génétiques sous-jacentes au développement de ces adénomes et aux formes familiales d’hyperaldostéronisme. Dans cette revue, nous décrivons les différentes anomalies génétiques associées à l’hyperaldostéronisme primaire et discutons les mécanismes par lesquels celles-ci conduisent à une augmentation de la production d’aldostérone et à la prolifération cellulaire, ainsi que les conséquences de ces connaissances sur le diagnostic et la prise en charge des patients

Genetic and Genomic Mechanisms of Primary Aldosteronism

International audienceAldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the main cause of primary aldosteronism (PA), the most frequent form of secondary hypertension. Mutations in ion channels and ATPases have been identified in APA and inherited forms of PA, highlighting the central role of calcium signaling in PA development. Different somatic mutations are also found in aldosterone-producing cell clusters in adrenal glands from healthy individuals and from patients with unilateral and bilateral PA, suggesting additional pathogenic mechanisms. Recent mouse models have also contributed to a better understanding of PA. Application of genetic screening in familial PA, development of surrogate biomarkers for somatic mutations in APA, and use of targeted treatment directed at mutated proteins may allow improved management of patients

Pathogenesis and treatment of primary aldosteronism

International audienceEarly diagnosis and appropriate treatment of primary aldosteronism, the most frequent cause of secondary hypertension, are crucial to prevent deleterious cardiovascular outcomes. In the last decade, the discovery of genetic abnormalities responsible for sporadic and familial forms of primary aldosteronism has improved the knowledge of the pathogenesis of this disorder. Mutations in genes encoding ion channels and pumps lead to increased cytosolic concentrations of calcium in zona glomerulosa cells, which triggers CYP11B2 expression and autonomous aldosterone production. Improved understanding of the mechanisms underlying the disease is key to improving diagnostics and to developing and implementing targeted treatments. This Review provides an update on the genetic abnormalities associated with sporadic and familiar forms of primary aldosteronism, their frequency among different populations and the mechanisms explaining excessive aldosterone production and adrenal nodule development. The possible effects and uses of these findings for improving the diagnostics for primary aldosteronism are discussed. Furthermore, current treatment options of primary aldosteronism are reviewed, with particular attention to the latest studies on blood pressure and cardiovascular outcomes following medical or surgical treatment. The new perspectives regarding the use of targeted drug therapy for aldosterone-producing adenomas with specific somatic mutations are also addressed

Deubiquitylation Regulates Activation and Proteolytic Cleavage of ENaC

The epithelial sodium channel (ENaC) is critical for sodium and BP homeostasis. ENaC is regulated by Nedd4-2–mediated ubiquitylation, which leads to its internalization; this process can be reversed by deubiquitylation, which is regulated by the aldosterone-induced enzyme Usp2-45. In a second regulatory pathway, ENaC can be activated by luminal serine protease–mediated cleavage of its extracellular loops. Whether these two regulatory processes interact, however, is unknown. Here, in HEK293 cells stably transfected with ENaC, Usp2-45 interacted with ENaC, leading to deubiquitylation of the channel and stimulation of ENaC activity >20-fold. This was accompanied by a modest increase in cell surface expression of ENaC and by proteolytic cleavage of αENaC and γENaC at their extracellular loops. When endocytosis was inhibited with dominant negative dynamin (DynK44R), channel density and γENaC cleavage were increased, but αENaC cleavage and ENaC activity were not augmented. When Usp2-45 was coexpressed with DynK44R, both αENaC cleavage and activity were recovered. In summary, these data suggest that Usp2-45 deubiquitylation of ENaC enhances the proteolytic activation of both αENaC and γENaC, possibly by inducing a conformational change and by interfering with endocytosis, respectively

Molecular genetics of Conn adenomas in the era of exome analysis

International audienceAldosterone-producing adenomas (APA) are a major cause of primary aldosteronism (PA), the most common form of secondary hypertension. Exome analysis of APA has allowed the identification of recurrent somatic mutations in KCNJ5, CACNA1D, ATP1A1, and ATP2B3 in more than 50 % of sporadic cases. These gain of function mutations in ion channels and pumps lead to increased and autonomous aldosterone production. In addition, somatic CTNNB1 mutations have also been identified in APA. The CTNNB1 mutations were also identified in cortisol-producing adenomas and adrenal cancer, but their role in APA development and the mechanisms specifying the hormonal production or the malignant phenotype remain unknown. The role of the somatic mutations in the regulation of aldosterone production is well understood, while the impact of these mutations on cell proliferation remains to be established. Furthermore, the sequence of events leading to APA formation is currently the focus of many studies. There is evidence for a two-hit model where the somatic mutations are second hits occurring in a previously remodeled adrenal cortex. On the other hand, the APA-driver mutations were also identified in aldosterone-producing cell clusters (APCC) in normal adrenals, suggesting that these structures may represent precursors for APA development. As PA due to APA can be cured by surgical removal of the affected adrenal gland, the identification of the underlying genetic abnormalities by novel biomarkers could improve diagnostic and therapeutic approaches of the disease. In this context, recent data on steroid profiling in peripheral venous samples of APA patients and on new drugs capable of inhibiting mutated potassium channels provide promising preliminary data with potential for translation into clinical care