The Aldosterone–Immune Axis in Primary Aldosteronism: Linking Adrenal Pathogenesis to Systemic Inflammation and Target-Organ Damage

Primary aldosteronism (PA) is the most common endocrine cause of secondary hypertension and is increasingly recognised as a systemic disorder extending beyond haemodynamic dysregulation. Accumulating evidence suggests that chronic autonomous aldosterone excess promotes maladaptive immune activation, establishing an aldosterone–immune axis that may contribute to cardiovascular, renal, and metabolic injury independently of blood pressure elevation. In some patients, glucocorticoid co-secretion may further amplify tissue-specific mineralocorticoid receptor (MR) signalling. Human and experimental studies indicate that aldosterone modulates both innate and adaptive immunity. Patients with PA demonstrate altered monocyte transcriptional profiles, enhanced vascular inflammatory activity, and increased pro-inflammatory cytokine signalling in monocyte-derived macrophages compared with blood-pressure-matched essential hypertension controls. Experimental models further show that sustained aldosterone exposure promotes macrophage M1 polarisation, dendritic cell activation, Th17 expansion, and regulatory T-cell suppression. These inflammatory changes are accompanied by oxidative stress, endothelial dysfunction, fibroblast activation, and extracellular matrix remodelling across cardiovascular and renal tissues. Emerging evidence is also consistent with a role for trained innate immunity, whereby prolonged aldosterone exposure may induce persistent epigenetic and metabolic reprogramming of monocytes and macrophages. Whether such reprogramming persists after biochemical correction by adrenalectomy or MR antagonism in human PA has not yet been directly demonstrated and remains an important open question. If confirmed, these mechanisms may help explain the partial irreversibility of target-organ damage despite successful treatment. This review synthesises current evidence linking adrenal somatic pathogenesis to systemic immune dysregulation and target-organ injury in PA. We propose that PA should be viewed not solely as a hypertensive disorder, but as a chronic fibro-inflammatory endocrine disease with important implications for early diagnosis, risk stratification, and targeted therapy. Future prospective human studies are needed to confirm the mechanistic hierarchy proposed and to identify the immunological targets most amenable to therapeutic intervention.