Sex differences in circadian regulation of kidney function of the mouse

Kidney function is regulated by the circadian clock. Not only do glomerular filtration rate and urinary excretion oscillate during the day, but the expressions of several renal transporter proteins also exhibit circadian rhythms. Interestingly, the circadian regulation of these transporters appears to be sexually dimorphic. Thus, the goal of the present study was to investigate the mechanisms by which the kidney function of the mouse is modulated by sex and time of day. To accomplish this, we developed the first computational models of epithelial water and solute transport along the mouse nephrons that represent the effects of sex and the circadian clock on renal hemodynamics and transporter activity. We conducted simulations to study how the circadian control of renal transport genes affects overall kidney function and how that process differs between male and female mice. Simulation results predicted that tubular transport differs substantially among segments, with relative variations in water and Na⁺ reabsorption along the proximal tubules and thick ascending limb tracking that of glomerular filtration rate. In contrast, relative variations in distal segment transport were much larger, with Na⁺ reabsorption almost doubling during the active phase. Oscillations in Na⁺ transport drive K⁺ transport variations in the opposite direction. Model simulations of basic helix-loop-helix ARNT like 1 (BMAL1) knockout mice predicted a significant reduction in net Na⁺ reabsorption along the distal segments in both sexes, but more so in males than in females. This can be attributed to the reduction of mean epithelial Na⁺ channel activity in males only, a sex-specific effect that may lead to a reduction in blood pressure in BMAL1-null males.NEW & NOTEWORTHY How does the circadian control of renal transport genes affect overall kidney function, and how does that process differ between male and female mice? How does the differential circadian regulation of the expression levels of key transporter genes impact the transport processes along different nephron segments during the day? And how do those effects differ between males and females? We built computational models of mouse kidney function to answer these questions.