Timing of food intake has become a critical factor in determining overall cardiometabolic health. We hypothesized that timing of food intake entrains circadian rhythms of blood pressure and renal excretion in mice. Male C57BL/6J mice were fed ad libitum or reverse feeding (RF) where food was available at all times of day or only available during the 12-hour lights-on period, respectively. Mice eating ad libitum had a significantly higher mean arterial pressure (MAP) during lights-off compared to lights-on (113 ± 2 vs 100 ± 2 mmHg, respectively; p < 0.0001); however, RF for 6 days inverted the diurnal rhythm of MAP (99 ± 3 vs 110 ± 3 mmHg, respectively; p < 0.0001). In contrast to MAP, diurnal rhythms of urine volume and sodium excretion remained intact after RF. Male Bmal1 knockout mice (Bmal1KO) underwent the same feeding protocol. As previously reported, Bmal1KO mice did not exhibit a diurnal MAP rhythm during ad libitum feeding (95 ± 1 vs 92 ± 3 mmHg, lights-off vs lights-on; p > 0.05); however, RF induced a diurnal rhythm of MAP (79 ± 3 vs 95 ± 2 mmHg, lights-off vs lights-on phase; p < 0.01). Transgenic PERIOD2::LUCIFERASE knock-in mice were used to assess the rhythm of the clock protein PERIOD2 in ex vivo tissue cultures. The timing of the PER2::LUC rhythm in the renal cortex and suprachiasmatic nucleus was not affected by RF; however, RF induced significant phase shifts in the liver, renal inner medulla and adrenal gland. In conclusion, the timing of food intake controls blood pressure rhythms in mice independent of Bmal1, urine volume or sodium excretion.

Histone deacetylase (HDAC) enzymes regulate transcription through epigenetic modification of chromatin structure, but their specific functions in the kidney remain elusive. We discovered that the human kidney expresses class I HDACs. Kidney medulla-specific inhibition of class I HDACs in the rat during high-salt feeding results in hypertension, polyuria, hypokalemia, and nitric oxide deficiency. Three new inducible murine models were used to determine that HDAC1 and HDAC2 in the kidney epithelium are necessary for maintaining epithelial integrity and maintaining fluid-electrolyte balance during increased dietary sodium intake. Moreover, single-nucleus RNA-sequencing determined that epithelial HDAC1 and HDAC2 are necessary for expression of many sodium or water transporters and channels. In performing a systematic review and meta-analysis of serious adverse events associated with clinical HDAC inhibitor use, we found that HDAC inhibitors increased the odds ratio of experiencing fluid-electrolyte disorders, such as hypokalemia. This study provides insight on the mechanisms of potential serious adverse events with HDAC inhibitors, which may be fatal to critically ill patients. In conclusion, kidney tubular HDACs provide a link between the environment, such as consumption of high-salt diets, and regulation of homeostatic mechanisms to remain in fluid-electrolyte balance.

Exposure to early life stress (ELS) is associated with a greater risk of chronic disease development including depression and cardiovascular disease. Altered gut microbiota has been linked to both depression and cardiovascular disease in mice and humans. Rodent models of early life neglect are used to characterize the mechanistic links between early life stress (ELS) and the risk of disease later in life. However, little is understood about ELS exposure and the gut microbiota in the young mice and the influence of the maternal inheritance of the gut microbiota. We used a mouse model of ELS, maternal separation with early weaning (MSEW), and normally-reared mice to determine whether the neonate microbiota is altered, and if so, are the differences attributable to changes in dam microbiota that are then transmitted to their offspring. Individual amplicon sequence variants (ASVs) displayed differential abundance in the microbiota of MSEW compared to normally-reared pups at post-natal day (PD)28. Additionally, ELS exposure reduced the alpha diversity and altered microbial community composition at PD28. The composition, levels of alpha diversity, and abundance of individual ASVs in the microbiota of dams were similar from MSEW or normally-reared cohorts. Thus, the observed shifts in the abundance of individual bacterial ASVs in the neonates and young pups are likely driven by endogenous effects of MSEW in the offspring host and are not due to inherited differences from the dam. This knowledge suggests that exposure to ELS has a direct effect on microbial factors on the risk of chronic disease development.

Exposure to early life stress (ELS) is associated with a greater risk of chronic disease development including depression, cardiovascular disease (CVD), and inflammatory bowel disease (IBD). Changes in the gut microbiota have been linked to IBD and CVD. Rodent models of early life neglect are used to characterize the mechanistic links between ELS exposure and the risk of disease later in life. However, little is understood about ELS exposure and the gut microbiota. We used a mouse model of ELS, maternal separation with early weaning (MSEW) and normally‐reared (NR) mice to determine whether the neonate microbiota is altered, and if so, whether the MSEW protocol induces changes in the dam microbiota that are then transmitted to their offspring. MSEW mice (n = 12) were subjected to maternal separation for 4 h per day on postnatal days (PDs) 2–5, and 8 h per day on PDs 6–16, and were subsequently weaned at PD17. NR mice (n = 13) remained undisturbed with dams until weaning on PD21. All mice were maintained on standard chow (NIH‐31; NSN 8710‐01‐005‐8438) following weaning. Paired‐end Illumina sequencing was conducted on colonic content from PD28 mice and DADA2 was utilized to infer and assign taxonomy to individual amplicon sequence variants (ASVs). The fecal microbiota of dams (n= 5) was also sequenced. Analysis of composition of microbiomes (ANCOM) detected 32 ASVs that had statistically different abundance in MSEW compared to NR mice at PD28. Five of the nine ASVs that increased in MSEW mice were classified as Clostridium senso stricto 1 or Lachnoclostridium, while none the of the 23 ASVs enriched in NR animals belonged to these taxa. Fifty‐seven percent (13 of 23) of the ASVs that had greater abundance in NR animals were classified as Lachnospiracea (other than Lachnoclostrium) or Ruminococcaceae. Compared to NR animals, MSEW PD28 mice had reduced phylogenetic diversity (18.7 ± 0.3 compared to 20.3 ± 0.3 in NR; P = 0.003) and Chao1ASV richness (175 ± 8 compared to 198 ± 8 in NR; P = 0.04). Microbial community composition was also altered at PD28 based permutational analysis of variance of Aitchison distance (F(1,24) = 2.29, P = 0.002). The composition, levels of diversity, and abundance of individual ASVs in the microbiota of dams were no different between MSEW and NR cohorts. Thus, the observed microbiota shifts in the young pups are likely driven by endogenous effects of MSEW in the offspring and independent of maternal inheritance. MSEW mice had lower microbial diversity and a reduction in Lachnospiraceae and Ruminococcaceae, which are important fermenters of short‐chain fatty acids (SCFAs). Nine different SCFAs were measured in plasma of PD28 mice and MSEW animals had reduced butyrate (P = 0.02) compared to NR controls. Butyrate promote colonic homeostasis as well as regulates metabolic health and CVD risk. Studies are on‐going to determine the impact of altered SCFA levels with ELS exposure. This study suggests a direct effect of ELS‐exposure on the gut microbiota, which may impact the risk of chronic disease...