Abstract 47: Circulating Human Sprr Increased Blood Pressure In Female Mice Fed A Low-fat Diet

Abstract

Elevated plasma soluble prorenin receptor (sPRR) is associated with essential hypertension and obesity-hypertension in men. Additionally, our laboratory previously found that the infusion of mouse sPRR elevates systolic blood pressure (SBP) in high-fat (HF) fed male mice through activation of the sympathetic nervous system but did not elevate SBP in HF-fed female mice. Interestingly, mouse sPRR infusion increased renal and hepatic angiotensinogen (AGT) and plasma renin concentration in female mice fed a low-fat diet. However, whether sPRR-activates the renin angiotensin system (RAS) and increases blood pressure in low-fat fed female mice remains to be investigated. Additionally, little is known concerning the influence of human sPRR on blood pressure in women. Therefore, we developed a humanized mouse model with high circulating human sPRR. Human sPRR-Myc-tag transgenic mice were bred with mice expressing Alb/Cre recombinase to induce human sPRR release in the circulation. Control and Alb-HsPRR female mice were fed a LF-diet for 8 months (n=11/groups). Body weight and body composition were examined and blood pressure assessed by radiotelemetry. Human sPRR-Myc-tag was detected in the liver of Alb-HsPRR female mice and plasma sPRR levels increased by 50-fold (CTL: 3.6±0.5 ng/ml, HsPRR:190.5±24.4 ng/ml; P<0.05), which validated the humanized mouse model. Elevated circulating human sPRR did not change body weight (CTL: 22.2±0.37, HsPRR: 23.0±0.32 g) or fat mass (CTL: 2.5±0.2, HsPRR: 3.1±0.2 g). Liver-derived human sPRR significantly elevated SBP in Alb-HsPRR compared to control female mice (Night SBP: CTL: 130.5±1.2 mmHg; Alb-HsPRR: 135.9±2 mmHg; P<0.05) and acute injection of AngII exacerbated SBP elevation. Interestingly, the decrease in blood pressure mediated by losartan was not different between Alb-HsPRR and control female mice (Night ΔSBP: CTL: -13.11±2.2 mmHg; Alb-HsPRR: -14.8±2.7 mmHg; P>0.05). Plasma AGT and renin activity were similar between Alb-HsPRR and control female mice. Therefore, whether the local RAS or the sympathetic nervous system are involved in human sPRR-mediated increase of SBP remains to be examined. Altogether, our results suggest an important role of circulating human sPRR in blood pressure control in women.