Abstract 064: 20-HETE Contributes to Vasoconstriction of Renal Microvessels and Sodium Retention in Cyp4a14-/- Mice, a Model of 20-HETE Dependent Hypertension

Abstract

20-HETE (20-Hydroxyeicosatetraenoic acid), is a cytochrome P450 (CYP) 4A-derived arachidonic acid metabolite. 20-HETE has been linked to both pro-hypertensive (via increased vasoconstriction, vascular remodeling and vascular injury of renal microvessels) and anti-hypertensive (inhibiting ion transport in the distal nephron) functions. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water soluble antagonist of the actions of 20-HETE on renal hemodynamics and sodium (Na) excretion in Cyp4a14 knockout (CYP4a14-/-) male mice. The CYP4a14-/- male mice display hypertension accompanied by increased vascular 20-HETE levels. Administration of 20-SOLA (10mg/kg/day in drinking water) normalized blood pressure (BP) in male Cyp4a14-/- mice at day 10 of treatment (124±1 vs. 153±2 mmHg in untreated male Cyp4a14-/- mice; p<0.05). The normalization of blood pressure was accompanied by transient increase in the urinary sodium excretion in the Cyp4a14-/- male mice (8.3±0.7 vs. 5.8±0.5 μmol/g body weight/day; p<0.05). Importantly, 20-SOLA increased glomerular filtration rate (GFR) of Cyp4a14-/- mice (2.38±0.05 vs. 1.88±0.18 μL/min/mg kidney weight, p<0.05) as opposed to no changes observed in the wild type (WT: (2.26±0.18 vs. 2.33±0.20μL/min/mg kidney weight). Evaluation of the renal blood flow (RBF) by laser Doppler flowmetry showed that treatment with 20-SOLA increased the RBF in Cyp4a14-/- mice by 12.3±4%, which remained unaltered in the WT. Additionally, the pressure-induced myogenic tone of isolated preglomerular microvessels was significantly elevated in Cyp4a14-/- mice; 20-SOLA treatment prevented the increase in myogenic responses. The natriuretic response to an isotonic saline loading challenge (10% of body weight, IP) was significantly attenuated in the Cyp4a14-/- mice as compared to the WT (35.5±2.8 vs. 57.4±8.3 percentage of Na load, p<0.05); this was corrected by 20-SOLA (61.7±5.7 percentage of Na load, p<0.05). These results confirm that 20-SOLA normalizes blood pressure of Cyp4a14-/- male mice and demonstrates that this is associated with increases in GFR, RBF and natriuresis.