DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Mechanisms of LOCal control of ALDOsterone production in the adrenal gland and their relevance for the pathogenesis of primary aldosteronism – LOCALDO

Submission summary

Arterial hypertension (HT) is one of the major risk factors for cardiovascular disease and has an important cost for society. Pathogenic mechanisms underlying HT are complex and include genetic and environmental, vascular and hormonal factors. Detection of secondary forms of HT is particularly important since it allows for the targeted management of the underlying disease.
Primary aldosteronism (PA) is the most common form of endocrine hypertension. Different adrenal diseases are responsible for PA: i) aldosterone-producing adenoma (APA or Conn's adenoma, ~50% of cases); ii) idiopathic hyperaldosteronism or bilateral adrenal hyperplasia (BAH, 30-40%); iii) unilateral primary adrenal hyperplasia (documented unilateral aldosterone secretion without detectable adenoma, 5-10%) and iv) aldosterone producing adrenal carcinoma in rare cases. Once the diagnosis of PA has been made, it is important to identify its etiology, in order to distinguish between surgically correctable forms (APA and unilateral primary adrenal hyperplasia) and forms to be treated pharmacologically (BAH). Patients with PA exhibit more severe left ventricular hypertrophy and diastolic dysfunction than patients with essential hypertension and a high prevalence of myocardial infarction, stroke and atrial fibrillation. Moreover, among unilateral forms of PA, hypertension is cured after surgery in less than 50% of patients. The understanding of the pathogenic mechanisms underlying PA is then essential to allow for the development of new diagnostic tools and biomarkers and for the identification of new therapeutic targets, concerning up to 10% of the hypertensive population.
Increasing evidence shows the relevance of local mechanisms regulating aldosterone production in the adrenal, as opposed to cardiovascular regulation by the renin-angiotensin system. Our research project aims to investigate pivotal aspects of the mechanisms implicated in local control of aldosterone secretion in the adrenal through a strategy that integrates functional genomics, mouse models and clinical studies, with the aim to better understand the physiopathology of PA for improved therapeutic intervention in hypertensive patients. The three French partners and the German partner implicated in the project have a long-lasting and very productive collaboration record in the field of the study of the physiopathology of aldosterone production. In the framework of their previous studies, critical advances have been made in the understanding of the physiopathology of PA, with the characterization of the in vivo role of potassium channels in the regulation of aldosterone secretion by the adrenal cortex and the identification of somatic mutations driving APA phenotype.
The first part of our project will focus on the identification of new genes involved in the pathogenesis of APA using the unique model of the Kcnk3 null mice previously characterized by our consortium, which present sex- and sexual hormone-dependent PA, and that allowed to identify a restricted set of genes with a potential role in the regulation of aldosterone secretion in the adrenal. Using a strategy that will integrate genetic, cell and animal studies, we will identify those genes that are relevant for aldosterone secretion in vivo and are associated to PA. In the second part of our project we will tackle the problem of the dissociation of hypersecretion and neoplastic nodule formation in pathological adrenals that overproduce aldosterone. We will produce the first mouse models with an altered function in genes whose homologs are implicated in APA and by genomic analysis we will identify genetic abnormalities in multinodular adrenals whose role in the nodulation process will be validated by producing ad hoc mouse models. We are confident that the results of our project will shed new light on the pathogenetic mechanisms of PA and allow to design new targeted therapies for this disease.

Project coordination

Enzo LALLI (Institut de Pharmacologie Moléculaire et Cellulaire CNRS)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IPMC CNRS Institut de Pharmacologie Moléculaire et Cellulaire CNRS
LP2M Laboratoire de PhysioMédecine Moléculaire CNRS
INSERM Institut National de la Santé Et de la Recherche Médicale
Uni Regensburg Université de Regensburg

Help of the ANR 595,000 euros
Beginning and duration of the scientific project: September 2015 - 48 Months

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