Abstract P077: Targeting Neutrophilia Is A Therapeutic Strategy To Regulate Blood Pressure

Abstract

Neutrophils are important innate immune cells that are relatively understudied for their contributions to blood pressure (BP) regulation. As neutrophilia is a clinical marker for various pathologies, we hypothesized that neutrophilia is also a feature of hypertension and curtailing neutrophilia is beneficial for lowering BP. Peripheral neutrophil levels were quantitated in Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats consuming either a low salt (0.3% NaCl) or high salt (2% NaCl) diet. Compared to R rats, S rats on a low-salt diet already exhibited neutrophilia (% neutrophils, 33.51±1.6 vs. 39.74±1.2, p<0.05). Introducing a high salt diet further potentiated the neutrophilia in S rats prone to salt-induced hypertension (% neutrophils, 48.21±0.6, p<0.05). These data suggest that neutrophilia is pro-hypertensive. To determine the possible mechanism for the pro-hypertensive effects of neutrophils, we investigated two major functions of neutrophils i.e., generation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs, web-like structures of expelled neutrophil DNA). Peripheral neutrophils stimulated with either PMA or LPS showed a ~ 3-fold induction of ROS and NETs, respectively, in S rats compared to R rats on a low-salt diet. Introducing a high-salt diet increased ROS and NETs (~2-fold), the extent of elevation being higher in S rats. Impressively, treatment of S rats on a high-salt diet with 1,3-butandiol [(β - hydroxybutyrate (βOHB, a ketone body) precursor] in the drinking water (20% v/v, 4 weeks) significantly lowered neutrophilia (vehicle: 1.74±0.5 vs βOHB: 0.73±0.3 x 10 9 cells/l, p<0.05) in tandem with their decreased BP (vehicle: 161.2±9.3 vs βOHB: 138.3±4.5 mmHg systolic BP, p<0.05). Interestingly, βOHB intervention also reduced neutrophil levels in R rats (vehicle: 1.15±0.5 vs βOHB: 0.95±0.5 x 10 9 cells/l), albeit to a lesser degree than S rats. Importantly, βOHB administration to S and R rats also reduced NETs and ROS (~2-fold), predominantly in S rats. Collectively, our data are the first to demonstrate that an exaggerated innate immune response via neutrophilia is pathological in hypertension, whereby curbing the neutrophilic response ( e.g., βOHB) could present therapeutic potential in lowering BP.