Lessons from marine osmoregulation: Comparative perspectives on salt-sensitive hypertension and human kidney–cardiovascular protection

Salt-sensitive hypertension (SSH) is a major contributor to cardiovascular and renal morbidity and is characterized by an impaired ability to excrete excess dietary sodium, resulting in extracellular fluid expansion, vascular dysfunction, and persistent elevation of blood pressure. In humans, SSH involves a complex interplay among defective renal pressure–natriuresis, maladaptive activation of the renin–angiotensin–aldosterone system and sympathetic nervous system, endothelial dysfunction, immune-mediated inflammation, and gut microbiota dysbiosis. In contrast, marine fishes inhabit environments containing extremely high sodium chloride concentrations while maintaining osmotic and cardiovascular stability without developing hypertension. Their resilience is enabled by highly specialized osmoregulatory systems involving seawater ingestion, intestinal desalination, active branchial salt secretion, epithelial ion transporters, aquaporin-mediated water recovery, and reduced renal dependence for sodium elimination. This review synthesizes current evidence on the pathophysiology of human SSH and the molecular physiology of marine fish osmoregulation to identify translational insights for kidney and cardiovascular protection. Particular attention is given to conserved ion transport pathways, including Na + /K + -ATPase, NKCC, CFTR, ANO1, aquaporins, claudins, and Na + /H + exchangers, highlighting their functional parallels across vertebrates. We further propose the Marine Osmoregulation-Inspired Sodium Resilience Model (MOISRM), a conceptual framework describing layered mechanisms of sodium tolerance and cardiovascular protection. Finally, we discuss translational opportunities involving dietary sodium reduction, potassium optimization, natriuretic therapies, RAAS inhibition, immunomodulation, microbiome-targeted interventions, and novel epithelial transporter targets. By integrating comparative physiology with translational medicine, this review positions marine osmoregulation as a promising framework for advancing therapeutic strategies against salt-sensitive hypertension and kidney injury.