Temporal misalignment of renal sodium transport promotes non-dipping blood pressure phenotypes

Abstract

Non-dipping blood pressure (BP) phenotypes are strongly associated with cardiovascular and renal morbidity, yet the physiological mechanisms governing nocturnal BP dipping remain incompletely understood. Experimental evidence suggests important roles for circadian timing, renal sodium handling, autonomic regulation, and sleep-wake behavior, but their interactions are difficult to isolate experimentally. We developed an integrated circadian-sleep/wake computational model of long-term BP regulation incorporating rhythmic modulation of renal sympathetic nervous activity, vascular tone, renin-angiotensin-aldosterone signaling, tubular sodium transport, and behavioral sleep-wake influences. The model reproduced a physiologically realistic healthy dipper phenotype with robust nocturnal BP reduction and daytime-predominant natriuresis. Component analyses demonstrated that vascular rhythmicity and sleep-wake modulation were dominant determinants of BP dipping, whereas intrinsic tubular sodium transport rhythmicity primarily regulated sodium excretion timing. Progressive reduction of tubular sodium rhythmicity redistributed natriuresis toward the nighttime period with modest effects on BP dipping. In contrast, altering the phase of tubular sodium transport produced marked effects on both natriuresis timing and BP regulation. Delayed tubular sodium transport phases shifted sodium excretion toward the nighttime period and converted the model from a dipper to a non-dipper phenotype despite preservation of rhythmic oscillations in other physiological systems. Sodium loading and enhanced salt-sensitive tubular sodium reabsorption amplified vulnerability when tubular sodium timing was delayed. These simulations suggest that physiological BP dipping emerges from coordinated temporal interactions among cardiovascular, renal, and behavioral regulatory systems. Non-dipping behavior may therefore arise not only from impaired rhythmicity, but also from misalignment among otherwise preserved physiological oscillators, particularly under sodium-loaded and salt-sensitive conditions.