Chronic circadian stress impairs blood pressure and sodium homeostasis in a diet- and sex-specific manner

This study investigates the effects of environmental circadian disruption and high-fat diet (HFD) on cardiovascular and renal functions in <i>Bmal1</i> knockout (KO) and wild-type (WT) rats. Under 12:12-h light:dark conditions, <i>Bmal1</i> KO males and females on a normal fat diet (NFD) exhibit lower mean arterial pressure (MAP) compared with WT. These genotype differences were attenuated after subjecting rats to a weekly 6 h advance in the 12:12-h light:dark protocol to induce chronic circadian stress (CCS). CCS modestly elevated MAP in males, eliminating pre-existing genotypic differences, whereas in females, CCS had no significant effects on MAP and heart rate. Under HFD, genotype-based MAP differences are attenuated, and sex differences in heart rate are diminished. CCS further elevated MAP in male <i>Bmal1</i> KO, accompanied by reduced blood pressure amplitude. Diurnal variations in sodium excretion are abolished post-CCS in both WT and <i>Bmal1</i> KO males on HFD. In <i>Bmal1</i> KO females, CCS combined with HFD disrupts sodium excretion rhythms, thus eliminating the protective effects seen on NFD. These findings highlight the complex interplay between circadian regulation, dietary fat, and environmental stress in modulating cardiovascular and renal physiology. This study further supports a "two-hit hypothesis," where CCS and HFD may synergistically disrupt sodium homeostasis and blood pressure circadian rhythms in both males and females.<b>NEW & NOTEWORTHY</b> We investigate the role of <i>Bmal1</i>, a core circadian clock gene, and diet in impairment of blood pressure and renal function during a chronic circadian stress protocol. This study finds that the endogenous molecular clock responds to circadian stress and high-fat diet in a sex-specific manner, warranting further investigation in the role of these systems in the regulation of blood pressure control and organ function.