The Circadian Clock Protein BMAL1 in the Kidney Contributes to Blood Pressure Control in Male Mice

Blood pressure (BP) regulation is influenced by the circadian clock as seen by its daily rhythm, with a peak occurring in the active phase and a dip during the rest phase. BMAL1 is a core circadian transcription factor which regulates the circadian clock feedback loop. BMAL1 also controls the expression of thousands of genes important for physiological functions. Others have shown that global BMAL1 knockout male mice have lower mean arterial pressure (MAP) and a loss of circadian rhythm compared to controls. Because the kidney is a critical regulator of BP, the goal of this study was to determine the BP phenotype of renal distal nephron-specific BMAL1 knockout mice (KO) vs. littermate controls (CNTL). KO were generated using Ksp-cadherin Cre. Histological analysis validated the BMAL1 KO model. MAP was measured by radiotelemetry. KO had 7 mmHg lower MAP compared to CNTL (103±2 vs. 110±0.2; P=0.03; N=4-5), however, the circadian rhythm of BP was apparent in both groups. There was no difference in activity or heart rate (P=0.7, P=0.1). Kidneys were collected at noon (midpoint of rest phase) for gene expression analysis, Table 1. HKa2 expression was increased in untreated KO vs. CNTL (1.7±0.2 vs. 1±0.1; P=0.01). We have previously linked HKa2 to renal Na handling and the mineralocorticoid response. Therefore, we assessed the BP response to a high salt diet plus mineralocorticoid treatment (HS/DOCP). MAP increased in both groups in response to HS/DOCP (P=0.03) where KO rose 6 mmHg (109±1) and WT only 2 mmHg (112±2). These results suggest that BMAL1 in the kidney plays a critical role in the regulation of BP but does not appear to contribute to the circadian rhythm of BP under the conditions tested.