Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada.
Cheriton School of Computer Science, University of Waterloo, Waterloo, Ontario, Canada.
Am J Physiol Renal Physiol. 2022 Dec 1;323(6):F675-F685. doi: 10.1152/ajprenal.00227.2022. Epub 2022 Oct 20.
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. 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.
肾脏功能受生物钟调控。肾小球滤过率和尿排泄不仅在白天呈波动变化，而且几种肾脏转运蛋白的表达也呈现昼夜节律。有趣的是，这些转运体的昼夜节律调节似乎存在性别二态性。因此，本研究的目的是探讨肾脏功能如何受性别和一天中时间的影响。为了实现这一目标，我们开发了第一个代表性别和生物钟对肾脏血液动力学和转运体活性影响的小鼠肾脏上皮水和溶质转运的计算模型。我们进行了模拟研究，以了解肾脏转运基因的昼夜节律控制如何影响整体肾脏功能，以及该过程在雄性和雌性小鼠之间有何不同。模拟结果预测，肾小管转运在各段之间存在显著差异，近端小管的水和 Na 重吸收以及厚升支的相对变化与肾小球滤过率同步。相比之下，远端段的转运变化要大得多，Na 重吸收在活跃期几乎增加了一倍。Na 转运的波动导致 K 转运呈相反方向变化。基本螺旋-环-螺旋 ARNT 样 1（BMAL1）敲除小鼠模型模拟预测，两性中远端段的净 Na 重吸收都显著减少，但雄性比雌性更为明显。这可归因于雄性中仅上皮 Na 通道活性的均值降低，这是一种性别特异性效应，可能导致 BMAL1 缺失雄性的血压降低。肾脏转运基因的昼夜节律控制如何影响整体肾脏功能，该过程在雄性和雌性小鼠之间有何不同？关键转运蛋白基因表达水平的昼夜节律调节如何影响白天不同肾单位段的转运过程？这些影响在雄性和雌性之间有何不同？我们构建了小鼠肾脏功能的计算模型来回答这些问题。
