Aldosterone: From Essential Tubular Regulator to Pathological Driver-Physiology, Disease, and Therapeutic Advances.

Aldosterone is a key regulator of sodium reabsorption, potassium secretion, and acid-base balance along the aldosterone-sensitive distal nephron (ASDN), where it exerts coordinated, segment-specific control over tubular transport. Although essential for volume conservation in terrestrial environments, aldosterone signaling has become maladaptive in modern sodium-rich contexts, contributing to systemic inflammation, fibrosis, and progression of cardiovascular and kidney disease. This review examines the regulation of aldosterone biosynthesis, the molecular diversity of mineralocorticoid receptor (MR) signaling, and the cellular mechanisms by which aldosterone shapes ion transport in the ASDN. A detailed classification of aldosterone-related disorders is presented, including hyperaldosteronism, pseudo-hyperaldosteronism, aldosterone resistance, and hypoaldosteronism. The therapeutic section focuses on MR overactivation in chronic kidney disease, critically appraising the clinical use of steroidal and non-steroidal MR antagonists. In addition, emerging strategies targeting aldosterone synthesis and downstream inflammatory pathways are discussed as potential approaches to address residual cardiorenal risk and the aldosterone breakthrough phenomenon. Together, these insights support a mechanistic reappraisal of aldosterone as both a physiological modulator and a pathologic driver, with implications for biomarker-guided, targeted therapy.