Circadian disruption via timing of food availability contributes to renal fibrogenesis in male, but not female mice

Abstract

Previous work from our lab showed that restricting food to the lights-on (inactive) period for less than one week causes circadian misalignment blood pressure and kidney excretory rhythms. Since circadian disruption increases risk of cardiometabolic disease, we hypothesized that long-term mistiming of food intake would lead to kidney injury. Male and female 5–7-week-old C57BL6/J mice were placed on the following feeding schedules: ad libitum (AL; 24-h food access), inactive time restricted (iTRF; 12h food access during the lights-on period only), or active time restricted (aTRF; 12h food access during lights-off period only) for 9 weeks. There were no differences in 24-hr food or water intake between the feeding groups. Male iTRF mice demonstrated a significant increase in renal fibrosis with 19.9±1.5% in cortex and 18.3±8.0% area staining positive as compared to AL mice with 8.2±2% and 8.6±1.2% in cortex and medulla, respectively (p < 0.05, n=3/group). In contrast, iTRF in female mice did not result in any discernable increases in renal fibrosis (7.5±2.5% and 8.9±0.3% in cortex and medulla, respectively) compared to AL mice (11.9±2.1% and 8.8±0.0% in cortex and medulla, respectively, (n=3/group). Similarly, pulse wave velocity (PWV), a measure of vascular stiffness (ultrasound) was significantly elevated only in iTRF males compared to either AL or aTRF mice (iTRF 2.4±0.1m/s, ad libitum 1.80.1m/s, aTRF 1.7±0.3m/s, p<0.05, n=3-4/group). To determine whether the observed renal fibrosis and vascular stiffness may be related to blood pressure, mean arterial pressure (MAP) was measured via telemetry in iTRF and aTRF animals. Data for both sexes were similar but combined due to lack of power to test for a sex effect (7/10 female iTRF, 6/11 female aTRF). At 4 weeks of iTRF, we observed a significant interaction of 24-h MAP rhythm between genotypes that was driven by lower MAP during the dark phase of iTRF compared to aTRF mice (Repeated measures 2-way ANOVA; genotype p=0.6793, time of day p<0.0001, interaction p<0.001) Finally, quantitative magnetic resonance revealed no significant differences between groups in body composition regardless of sex, suggesting that circadian disruption by TRF does not result in caloric restriction or weight loss. Together, these data demonstrate that circadian disruption by restricting food access results in significant fibrosis in both kidney and vascular tissues preferentially in male, but not female mice. These changes appear to be independent of changes in blood pressure. PRIME T32 DK116672 (J. Benjamin), AHA Career Development Grant (P. Pati), P01HL136267 (D. Pollock, J. Pollock) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.