Abstract 079: Long-term Circadian Disruption Via Food Availability Leads To Kidney Damage

Abstract

Circadian disruption (CD) is a risk factor in cardiovascular disease although we know little about its effects on the kidney. Previous work from our group showed that short-term CD in mice by restricting food availability to the daytime is sufficient to invert diurnal blood pressure rhythms yet kidney excretory function remained aligned with the light-dark cycle. Thus, we hypothesize that long-term CD will result in kidney damage. After putting C57BL/6 mice on a regular 12:12 light:dark cycle were placed on an inactive time-restricted feeding (iTRF, 12h food access during the day/lights on) or ad libitum feeding protocol for 8 weeks. During the final week, male and female iTRF mice ate significantly less during the 24-hour day compared to ad lib feeding (male iTRF 6.1±1.4g/day vs. ad lib 9.1±0.9g/day, p<.0001, n=9 for both groups; female iTRF 6.4 ±0.7 g/day, vs. ad lib 8.3±1.5g/day, p<0.01, n=9 and 8, respectively). Both sexes had an inversion in their diurnal water intake rhythms but maintained normal diurnal urinary water excretion. Aldosterone (aldo) and endothelin-1 (ET-1) contribute to circadian timing of sodium transport systems in the collecting duct. While male iTRF mice maintained their diurnal rhythm of aldosterone excretion (2.0±1.4ng/hr in light, p=0.06; 7.8±3.1ng/hr in dark, p=0.37, n=6), female iTRF mice lost their diurnal rhythm (4.4±2.7ng/hr in light, p=0.85; 4.4±3.1ng/hr in dark, p=0.11, n=6). Male mice with iTRF had significantly lower ET-1 excretion, but maintained the diurnal variation. In contrast, female iTRF mice demonstrated an inverted ET-1 excretion pattern (18.5±6.3ng/hr in light vs. 7.3±2.9ng/hr in dark, p=0.03, n=3) compared to ad lib fed mice (18.9±2.1ng/hr in light vs. 33.7±5.6ng/hr in dark, p=0.01, n=3). Picrosirus red staining of kidneys revealed a striking increase in glomerular and interstitial fibrosis in iTRF male mice as compared to their ad lib counterparts. In contrast, iTRF female mice appeared to be completely protected from increased fibrosis. These results support our hypothesis that long-term CD due to timing of food intake exacerbates kidney damage. However, females were protected against renal fibrosis, perhaps due in part to an ability to better modulate kidney rhythms in response to food timing.