Abstract P1126: Neutrophil Extracellular Traps: New Players in Hypertension

Abstract

Aberrant immune responses are linked to hypertension; yet, neutrophils remain relatively understudied. Both neutrophilia and elevated neutrophil-to-lymphocyte (N/L) ratio are used as clinical biomarkers of hypertension. Likewise, neutrophilia is reported in spontaneously hypertensive rats. Whether these features are associated with an increase in neutrophil extracellular traps (NETs) generation is unknown. We hypothesized that neutrophilia and NETs directly correlate with hypertension whereby lowering neutrophilia and NETs are therapeutically beneficial to lower blood pressure (BP). Herein, we used various, genetic rat models divergent in BP to study the neutrophil-hypertension axis. These include the Dahl Salt-Sensitive (S) and Resistant (R) rats, and the low (LCR) and high (HCR) exercise capacity runner rats. LCR (2.1±0.3 10 9 /l) and S rats (1.2±0.5 10 9 /l) exhibited neutrophilia compared to HCR (0.98±0.5 10 9 /l) and R rats (1.04±0.5 10 9 /l), p<0.05, respectively. To determine whether neutrophil function was also augmented, peripheral neutrophils were stimulated with either PMA or LPS to induce ROS and NETs generation, respectively. LCR and S rats generated ~2-3 folds more ROS and NETs compared to their HCR and R counterparts. Intriguingly, LCR (11.4±1.0 U/ml) displayed reduced DNase I activity than HCR (17.8±0.8 U/ml), p<0.05, which indicated an inadequate clearance of NETs. Systemic and renal lipocalin-2 were 2-3 folds higher in the S rats compared to R rats, suggesting low-grade inflammation associated with NETs overabundance. Introducing a high-salt diet to S and R rats further potentiated neutrophilia, ROS and NETs, the extent of elevation being higher in S rats. Opposingly, oral administration of β-hydroxybutyrate (βOHB; a hypotensive ketone body) to S and R rats reduced neutrophilia, NETs and ROS. Similarly, subjecting LCR to exercise and fasting, both of which lower BP and increase βOHB, substantially attenuated neutrophilia, NETs and ROS. Collectively, our results demonstrate that NETs are an important feature directly linked to elevated BP in a strain-independent manner. Thus, blunting neutrophil responses through dietary intervention or exercise could serve as a novel therapeutic strategy against hypertension.