Bmal1 and the sex specific role of oxalate metabolism in female rats

The endogenous molecular clock regulates organ function, predicts physiological needs, and controls several metabolic pathways. Of this, brain and muscle ARNT-like 1 ( Bmal1 ) is a crucial component, and its loss in preclinical models results in dysfunctional metabolic and transcriptomic rhythms, including those in the liver and kidney–organs critical in kidney stone formation (KSF). The amount of oxalate excreted in urine is a known risk factor for calcium oxalate KSF. Endogenous oxalate synthesis is an important source of urinary oxalate and involves liver enzymes, including alanine-glyoxylate aminotransferase (AGT), glycolate oxidase (GO), and glyoxylate reductase (GR). Currently, there is limited understanding of the interactions between the molecular clock and KSF. We hypothesized that Bmal1 regulates liver oxalate metabolism. We measured urinary oxalate excretion by ion chromatography coupled with mass spectrometry (ICMS) in adult rats lacking Bmal1 ( Bmal1 -KO) and age/sex-matched wild-type (WT) controls (n=7-8 per group) during their active and inactive periods. The activity of the liver peroxisomal enzyme, AGT, was measured in liver peroxisome fractions in the active (ZT13) and inactive (ZT1) periods. There was a diurnal pattern in urinary oxalate excretion, with higher excretion at night in Bmal1 -KO male and females (2-way ANOVA, p Time , = 0.002 for males). Additionally, Bmal1 -KO females had higher urinary oxalate excretion compared to WT females (2-way ANOVA, p Time , = 0.008, p Genotype =0.02). The activity of AGT was higher in both Bmal1 -KO male and females (x̄ WT = 8.2 nm/min/mg, x̄ KO = 20.7 nm/min/mg) compared with WTs, with higher activity in females compared to males. These results suggest that Bmal1 may act as a temporal mediator in endogenous oxalate metabolism in a sex-specific manner. Future work will look at the roles of other enzymes involved in endogenous oxalate metabolism using a combination of labeled oxalate precursors and specific enzyme activity assays. NIH R25 DK 112731 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.