Abstract P176: Hypertension is Mediated by an Angiotensin II-Dependent Mechanism in Adipocyte Prorenin Receptor KO Female Mice and by the Para-Sympathetic Nervous System in Adipose Prorenin Receptor KO Male Mice

Abstract

Obesity and lipodystrophy models, two opposite ends of adipose tissues dysfunction, can lead to hypertension and constitute relevant tools to decipher mechanisms involved in blood pressure control. Since sex related difference exists in blood pressure control, we aimed to determine whether the mechanism leading to hypertension in adipocyte prorenin receptor (PRR) KO mice was similar in male and female mice. Adipocyte PRR KO and control littermate (CTL) male (n=8 to 9 mice/group ) and females mice (n=6 to 7 mice/group) were fed a high fat diet. The systolic blood pressure (SBP) was evaluated by radiotelemetry. Adipose-PRR KO significantly increased SBP in both male and female mice (Day SBP, CTL male=122.2±1.9 mmHg, KO male=128.7±2.4 mmHg, P=0.046; CTL female=120.4±0.9 mmHg, KO female=125.5±1.9 mmHg, P=0.03). Acute losartan injection, an AT 1 R inhibitor, blunted elevated SBP in both CTL female and male mice. Interestingly, losartan decreased SBP to a greater extent in adipose PRR KO female mice compared with control female mice (Delta SPB, CTL male=-7.9±1.5 mmHg; KO male=-6.4±3.1 mmHg, P=0.68; CTL female=-5.3±1.9 mmHg; KO female=-14.2±0.9 mmHg, P=0.015). To assess the contribution of the autonomic nervous system, male and female mice were injected with propranolol, atropine and chlorisondamine. The tachychardic response to atropin was significantly greater in adipose-PRR KO male mice compared with control male mice (Delta Heart Rate, CTL male=+114.2±12.1 bpm; KO male=+156.0±11.1 bpm, P=0.023) but did not change in adipose-PRR KO female mice compared with control female mice (Delta Heart Rate, CTL female=+84.8±10.1 bpm; KO female=+89.8±21.3 bpm, P=0.85). In conclusion, our data strongly suggest that the elevation of SBP in adipose PRR KO mice is mediated by an AngII-dependent mechanism in female mice and by the para-sympathetic nervous system in male mice. These results support the importance of sex-specific approach for the development of personalized drugs in hypertension treatment.