Loss of the liver circadian clock affects the expression of intrarenal renin-angiotensin system components

TL;DR

This study shows that the liver's circadian clock influences kidney functions related to blood pressure regulation, even when the clock is missing.

Contribution

The study reveals an alternative communication pathway between the liver and kidney that regulates the kidney's renin-angiotensin system.

Findings

Daily fluctuations in intrarenal renin-angiotensin system components persist in mice without a liver circadian clock.

Reduced expression of the Na+/H+ exchanger 3 in the kidney correlates with lower blood pressure in these mice.

Abstract

The intrarenal renin-angiotensin system (irRAS) regulates Na+ and fluid retention to counteract low blood pressure. Some of its components are expressed with daily rhythms. The circadian metabolism and physiology of the liver can synchronize gene expression in other organs. Hence, we tested whether the liver circadian oscillator could coordinate daily fluctuating expression of irRAS components. To this end, we used two different knock-out mouse strains lacking circadian oscillators specifically in hepatocytes to investigate the impact of this inactivation on their irRAS. Surprisingly, daily fluctuations in expression of many irRAS components in these animals were still detectable but with different phases. The data indicate that signals from liver can synchronize most of the irRAS components tested independent of its circadian oscillator. Both hepatocyte-specific knock-out mouse strains had reduced expression of the Na+/H+ exchanger 3 (Nhe3) in kidney, which may explain the ~ 25% reduction in their systolic and diastolic blood pressure. Taken together, our study suggests that mice can use an alternative way of communication between liver and kidney to regulate the daily fluctuations of irRAS components. Identification of this mode of communication could help to better understand the pathophysiology of the kidney, which affects fluid balance and blood pressure.

The online version contains supplementary material available at 10.1038/s41598-025-34303-w.

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