Circadian rhythms in glomerular filtration govern natriuresis and diuretic responsiveness

Kidney function exhibits circadian rhythms that arise in part from clock-gene-mediated regulation of renal transporter proteins. Key Na⁺ transporters under circadian control include NHE3, SGLT1, NKCC2, NCC, and ENaC, which are targeted by commonly prescribed diuretics. The present study uses computational models of nephron transport to investigate how circadian regulation influences renal function and the natriuretic responses to diuretics in normotensive and Ang II-induced hypertensive rat kidneys. Simulations of conditional Bmal1 knockdown predict marked attenuation of transporter oscillations, segment-specific changes in mean transporter abundance, and a loss of the normal dipping pattern in Na⁺ excretion. In the hypertensive kidney, Na⁺ transport is redistributed from proximal to distal segments, increasing overall natriuresis and diuresis while largely preserving the phase of excretory rhythms when filtration retains its circadian oscillation. Across normotensive and hypertensive conditions, the model predicts that the phase and amplitude of daily excretory rhythms are primarily determined by oscillations in single-nephron glomerular filtration rate (SNGFR). When SNGFR exhibits a normal circadian rhythm ("dippers"), diuretic-induced natriuresis is greatest during the active phase. In contrast, when SNGFR rhythms are absent ("non-dippers"), the time of maximal natriuretic response shifts to the inactive phase, when transporter expression is lowest. Thus, the optimal time of diuretic administration depends on circadian phenotype rather than clock time alone. These findings highlight the importance of renal circadian regulation in determining diuretic responsiveness and suggest that dosing strategies may need to account for individual dipping status.