Integrated mechanisms linking sodium–potassium imbalance to salt‐sensitive hypertension

Abstract

Salt-sensitive hypertension (SS-HT) represents a clinically heterogeneous and mechanistically distinct phenotype of blood pressure dysregulation in which sodium intake disproportionately elevates blood pressure. SS-HT affects up to 50%-60% of individuals with hypertension globally, with an even greater burden among individuals of African ancestry, postmenopausal women, and those with obesity or metabolic syndrome. SS-HT arises from multifactorial dysregulation of renal, vascular, and immune systems. Central to its pathophysiology is aberrant activation of the epithelial sodium channel (ENaC), which drives sodium reabsorption in the distal nephron. ENaC activity is enhanced by both aldosterone-dependent and -independent mechanisms. Concurrently, high dietary sodium induces oxidative stress through NADPH oxidase-mediated reactive oxygen species (ROS) production, disrupts nitric oxide (NO) signaling, and activates antigen-presenting dendritic cells, triggering T-cell-mediated vascular and renal inflammation. This review proposes a systems-level framework in which SS-HT reflects the convergence of ENaC hyperactivation, immunometabolic priming, and hormonal modulation, shaped by sex, race, and dietary sodium-potassium imbalances. Understanding SS-HT as a multifaceted systems disorder opens new avenues for personalized prevention and treatment. Population-specific interventions, such as ENaC-targeting therapies, potassium-enriched diets, and sex and ancestry-informed modulation of the renin-angiotensin-aldosterone system (RAAS), represent promising strategies for precision medicine.