Genetic Mechanisms of Aldosterone-Related Disorders

Arterial hypertension (HT) is the silent killer No. 1, accounting for >10 million deaths/year from stroke, ischemic heart disease, chronic kidney disease and other vascular causes. Although HT treatment can reduce incident adverse cardiovascular events, optimal blood pressure control is not being achieved in up to two thirds of patients. Detection of secondary forms of HT is key to targeted management of the underlying disease and prevention of cardiovascular complications. PA, due to autonomous aldosterone production from the adrenal gland due to an aldosterone producing adenoma (APA) or bilateral adrenal hyperplasia (BAH), is the most frequent form of secondary HT and its prevalence increases with HT severity, from ~5% in primary care to up to 25% in treatment-resistant HT. Due to the complexity of the work-up, fewer than 1% of patients are ever diagnosed and appropriately treated, thus contributing to a high burden of cardiovascular complications. The overall hypothesis of our research is that understanding the mechanisms responsible for aldosterone production and function will allow to improve diagnosis and treatment of arterial hypertension in the general population.

In this context, research performed by our team is entirely devoted to improve diagnosis and treatment of hypertension, by developing an integrative research program spanning from basic science in cell and animal models to genetic and clinical investigations in patients. The overarching aim of our program is to unravel the genetic and mechanistic architecture of blood pressure regulation in relation to aldosterone in order to generate knowledge translatable to clinics. Our vision is that understanding mechanisms driving inappropriate aldosterone production and its role in the pathophysiology of hypertension and cardiovascular complications is a critical gap in knowledge and unmet medical need. To achieve our goal, we apply the most recent genomic technologies on unique cohorts of patients with access to standardized clinical and biological information, tissue and DNA samples, integrated within national and international networks and programs. An original interdisciplinary approach combines complementary expertise in genetic and clinical investigation with high throughput genomic approaches, molecular, cellular and animal experiments. This strategy has been extended to the development of multi-omics biomarker for patients with HT in the context of two EU-funded programs coordinated by MC Zennaro, the Horizon 2020 research and innovation project ENSAT-HT (www.ensat-ht.eu) and the Horizon Europe funded program HT-ADVANCE (www.ht-advance.eu).

Recent results

The main aim of our research is to understand mechanisms driving inappropriate aldosterone production and its role in the pathophysiology of hypertension (HT) and cardiovascular complications to develop precision medicine in HT.

Our team has made major contributions to the knowledge of the genetic and pathogenic mechanisms of PA, revealing new genes responsible for familial and sporadic forms of the disease (Fernandes-Rosa et al, Nat Genet 2018, Zhou et al, Nat Genet 2021). We have performed the first GWAS study on PA that suggests that common genetic variation may underlie dysregulated aldosterone production in the general population, leading to PA in extreme cases (Le Floch et al, Nature communications 2022). We have developed cell (Fedlaoui et al, Hypertension 2025) and animal models mimicking KCNJ5 mutations to investigate their functional impact and pathogenic role in APA. Furthermore, we established the role of the mineralocorticoid receptor (MR) in parietal epithelial cells to drive glomerular disease (Lazareth et al, Kidney Int 2025). The vision of the team has been extended from genetic and mechanistic studies to the development of omics-derived biomarkers for improved diagnosis and treatment of patients with hypertension (Reel et al, EBioMedicine 2022). Maria-Christina Zennaro has also contributed to the international clinical guidelines for PA (Adler et al, J Clin Endocrinol Metab 2025) and coordinated the roadmap for adrenal and cardiovascular endocrinology, shaping future directions in the field (Husebye et al, Eur J Endocrinol 2025).

Projects

Our current work addresses the following aims: 1) To develop precision medicine in hypertension by integrating genetic, molecular, and clinical investigations and to develop multiomics biomarkers for improved diagnosis and treatment; 2) To investigate how diet and menopause modulate adrenal steroidogenesis and aldosterone regulation to clarify their role in cardiometabolic risk and enable targeted prevention strategies; 3) To uncover molecular mechanisms of aldosterone-driven tissue injury by integrating transcriptomics, post-translational modifications, and microRNA regulation to identify novel therapeutic targets.

Axis #1: Precision medicine in hypertension (Maria-Christina Zennaro)

This axis aims at improving diagnosis and treatment of hypertension, by developing an integrative research program spanning from basic science in cell and animal models to genetic and clinical investigations in patients. Recent data reveal a continuum of dysregulated aldosterone production, ranging from mild forms to overt PA, affecting a substantial proportion of patients with HT. Results from our GWAS provide a mechanistic explanation to this continuum, suggesting that common genetic variation may regulate key adrenocortical processes (Le Floch et al., 2022). To uncover the mechanisms of adrenocortical dysfunction and aldosterone excess, we will investigate the genetic architecture of aldosterone dysregulation, from monogenic forms to genetic susceptibility in the general population alongside the somatic genetics of APA and elucidate the interconnected mechanisms that regulate adrenocortical homeostasis and function. To this purpose, we use cutting-edge genetics and genomics methodology on unique populations with PA, genetically modified mouse and newly developed human adrenal cell models. In parallel, we develop multi-omics (MOMICS) stratification biomarkers directed at patients with arterial HT in order to implement efficient and cost-effective therapy and prevent cardiovascular complications, in the context of the Horizon Europe funded HT-ADVANCE collaborative project coordinated by MC Zennaro (https://ht-advance.eu/).

Axis #2: Decoding Pathophysiological Regulation of Adrenal Function: impact of diet and menopause (Sheerazed Boulkroun)

This axis seeks to uncover how dysregulated aldosterone production drives cardiovascular and metabolic complications, bridging molecular insights with therapeutic innovation. We explore the molecular mechanisms underlying the development of PA and have generated an inducible mouse model of hyperaldosteronism to dissect its key molecular drivers, with a particular focus on KCNJ5 mutations, the most common genetic cause of PA. This model enables us to assess associated cardiometabolic outcomes, compare different therapeutic strategies, and explore transgenerational effects of maternal hyperaldosteronism on offspring health. By integrating in vivo and in vitro approaches, we aim to identify actionable targets for precision medicine. Postmenopause is a critical window for cardiometabolic risk, exacerbated by weight cycling. We hypothesize that adrenal dysfunction amplifies the risk through aldosterone and mineralocorticoid receptor signalling. Our objectives include identifying molecular signatures of “deleterious memory” in adrenal and adipose tissue and testing the preventive potential of innovative therapies. This axis aims to deliver mechanistic insights and innovative therapies for hypertension, metabolic syndrome and cardiovascular disease, conditions with profound global health implications. (Project funded by grants from Phenomin, the Université Paris Cité and the Société Française d’Endocrinologie).

Axis #3: Mechanisms of Aldosterone-Mediated End-Organ Damage: Integrating Transcriptomics, Post-Translational Modifications, and microRNA Regulation (Fabio Fernandes-Rosa)

This axis explores the multi-scale regulation of aldosterone action and biosynthesis, focusing on its mechanisms in vascular damage and its role in blood pressure and electrolyte balance. We investigate how aldosterone acts on the aldosterone-sensitive distal nephron using single-nucleus RNA sequencing to map gene expression changes at cellular resolution, revealing functional heterogeneity, novel aldosterone-responsive genes, and feedback loops in mineralocorticoid signaling. In parallel, we study how O-GlcNAcylation, a dynamic post-translational modification, influences aldosterone biosynthesis and vascular responses. Through transcriptomic, proteomic, and functional analyses in cellular and animal models, we aim to clarify its role in hypertension and adrenal disorders. Finally, we examine the contribution of miR-139-5p to adrenal cortex function and the pathogenesis of primary aldosteronism. Using transgenic models, organotypic cultures, and adrenal tumor samples, we seek to define its function and therapeutic potential. Together, these studies integrate transcriptional, epigenetic, and post-translational mechanisms to advance understanding of aldosterone physiology and pathophysiology. (Project funded by CAPES-COFECUB 2025 and grants from the Fédération Française de Cardiologie and the Société Française d’Endocrinologie).