Abstract P380: Inverse Circadian Pattern in the Renal Generation of Tumor Necrosis Factor-Alpha (TNFå) and Angiotensinogen (AGT) in Salt-Sensitive Hypertension (SSH) Induced by Angiotensin II (AngII) in Mice

Abstract

Individuals with SSH show a non-dipping blood pressure (BP) during the inactive night period, a phenomenon which is significantly associated with enhanced cardiovascular morbidity and mortality. However, the pathophysiological mechanism for this phenomenon is not yet clearly understood. Chronic AngII administration in mice (reversed circadian rhythm) induced SSH with an increase in intra-renal AGT formation, a response that was exaggerated in TNFα receptor type 1 (TNFR1) knockout mice, indicating that renal AGT formation is suppressed by TNFR1 activation by TNFα. The present study examined the hypothesis that AngII-induced TNFα formation follows a circadian pattern with increases during the active period compared to the inactive period, that facilitates less AGT formation during the active period. Experiments were performed in mice chronically treated with or without AngII (25 ng/min; osmotic mini-pump) + high salt (4% NaCl) intake for 4 weeks that increased BP from 90±2 to 108±3 mmHg (tail-cuff method). Circadian rhythm in urinary parameters was assessed by 12 hour collections of urine using metabolic cages during the active night period (7PM to 7AM) and the inactive day period (7 AM to 7 PM). In normal mice (n=6), urinary excretion of TNFα (uTNFα) was higher (0.5±0.2 vs 0.13±0.08 pg/hour) but urinary excretion of AGT (uAGT) was lower (0.28±0.18 vs 0.46±0.14 ng/hour) during the active period compared to that during the inactive period. This inverse relationship between uTNFα and uAGT was exaggerated in AngII+HS treated mice (n=6). From the baseline (0 week) to the 2nd and 4 th week period, there were marked incremental changes in uTNFα during active periods (0.68±0.20 to 14.2±5.4 and 44.6±14.6 pg/hour) which were less during inactive periods (0.73±0.48 to 10.3±3.3 and 12.1±4.7 pg/hour). Interestingly, uAGT changed minimally during active periods (0.21±0.14 to 0.05±0.04 and 1.42±0.97 ng/hour) but increased significantly during inactive periods (0.32±0.14 to 1.57±0.71 and 3.98±1.67 ng/hour). These data suggest that an increase in TNFα generation suppresses intra-renal AGT formation during active periods but this phenomenon is inversed during inactive periods. The increase in AGT during the inactive period could lead to a non-dipping BP pattern in SSH.