Abstract TAC231: The immune ET-1/ET A receptor axis modulates blood pressure responses and renal function in males, but not females.

Although immune cell dysregulation and exaggerated levels of endothelin-1 (ET-1) are critical for the development of hypertension, there is an important gap of knowledge regarding the involvement of the immune ET-1 system in the progression of this condition. Dendritic cells (DCs) and T cells are deeply involved in hypertension, and can respond to ET-1 through receptors on their surface. However, if activation of the ET-1/ET A axis in DCs and T cells is critical for rising blood pressure and deteriorating cardio-renal function in hypertension is unclear. Additionally, if this axis contributes to this pathology similarly in both sexes remains unknown. We hypothesized that (1) stimulation of the ET-1/ET A axis on DCs and T cells is critical for the development and progression of hypertension and deterioration of cardio-renal function, and (2) the immune ET-1/ET A axis plays a more prominent role in driving hypertension in males than females. Mice lacking ET A receptor on DCs (DC ET A KO) or T cells (T cell ET A KO) and floxed ET A control mice received the nitric oxide synthase inhibitor L-NAME (0.5 mg/mL, drinking water) for 3 wks. Systolic blood pressure (SBP) was monitored via tail cuff plethysmography (3 times/wk) and changes in renal function via glomerular filtration rate (GFR) at baseline and after L-NAME treatment. Lack of ET A receptor resulted in similarly decreased baseline SBP in male DC ET A KO and T cell ET A KO mice (Floxed ET A vs. DC ET A KO: 120.2±2.2 vs. 113.2±1.6 mmHg, n=10/group, p=0.25; floxed ET A vs. T cell ET A KO: 118.4±2.6 vs. 110.2±3.1 mmHg, n=11/group, p=0.058). However, lack of immune cell ET A receptor led to ameliorated responses to L-NAME in males (Floxed ET A vs. DC ET A KO: 140.6±3.6 vs. 124.9±2.5 mmHg, n=10/group, p=0.003; floxed ET A vs. T cell ET A KO: 135.2±2.0 vs. 118.0±4.1 mmHg, n=11/group, p=0.002). No difference among genotypes was found in females at any time point. Renal function was unchanged in all groups after L-NAME treatment, but it increased in male T cell ET A KOs (baseline vs. L-NAME: 288.8±33 vs. 436.0±34μL/min). Our findings suggest that activation of the immune ET-1/ET A axis is important in regulating SBP in response to a hypertensive insult, but only in males. Also specific to males, lack of ET A receptor on T cells enhances renal function during hypertension. Our data indicate that the use of ET A receptor antagonists may be more effective in men for protection against hypertension and its associated renal damage.