Aldosterone–mineralocorticoid receptor interactions: new insights and therapeutic perspectives in primary aldosteronism

Aldosterone exerts its effects primarily through the activation of the mineralocorticoid receptor (MR), a nuclear receptor that mediates sodium reabsorption in the kidney and contributes to cardiovascular and renal injury through fibrosis, inflammation, and vascular remodeling. Recent evidence indicates that MR activation is not solely dependent on circulating aldosterone levels but can also be influenced by factors such as high salt intake and hyperglycemia. Mineralocorticoid receptor antagonists (MRAs) remain the cornerstone of the pharmacological MR blockade. Newer nonsteroidal MRAs offer greater receptor selectivity and improved tolerability. Finerenone has been demonstrated to have cardiovascular and renal benefits in patients with chronic kidney disease and type 2 diabetes, whereas esaxerenone has shown potent antihypertensive and antialbuminuric effects across diverse patient populations, including those with resistant hypertension and primary aldosteronism (PA), particularly in combination with renin-angiotensin system inhibitors. Aldosterone synthase inhibitors (ASIs) have recently emerged as novel therapeutic agents. Selective inhibition of aldosterone synthase (CYP11B2) reduces aldosterone production and may suppress both genomic and non-genomic effects. Several ASIs have been investigated in clinical trials for efficacy and safety in patients with resistant hypertension, chronic kidney disease, and PA. PA is characterized by excessive MR activation and is associated with an increased risk of cardiovascular and renal complications. Recent studies have highlighted the importance of post-treatment renin levels as a marker of therapeutic response, as reflected in Primary Aldosteronism Medical Treatment Outcome (PAMO) criteria. Nevertheless, clinical outcomes remain the most relevant endpoints, and MRAs continue to be a central therapeutic strategy in PA management. Mineralocorticoid receptor activation by aldosterone and modulatory factors: ASI aldosterone synthase inhibitor, ALDO aldosterone, HTN hypertension, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, PA primary aldosteronism.