(560.15) Adipose-derived human soluble (pro)renin receptor causes resistance to Losartan treatment in high-fat diet male and female mice

Poster Board Number: E171

Kellea Nichols (University of Kentucky), Gertrude Arthur (University of Kentucky), Terry Hinds (University of Kentucky), Frederique Yiannikouris (University of Kentucky)

Obesity, affecting more that 37% of the US, contributes to hypertension.  Despite the use of one or more anti-hypertensive treatments, 48% of the hypertensive population remains with resistant hypertension, which prompts the development for new therapeutic targets. We demonstrated that obesity increased the expression of prorenin receptor (PRR) in the adipose tissue and elevated plasma soluble PRR (sPRR). In addition, the infusion of mouse sPRR increased blood pressure in male mice fed high fat-diet (HF); indicating that adipose-derived sPRR could increase circulating sPRR and contribute to hypertension. However, there is a critical gap in the functional role of human sPRR in obesity-hypertension. In this study, we aim to define whether adipose-derived human sPRR contributes to obesity-hypertension.

Human sPRR-Myc-tag transgenic mice were bred with mice expressing adiponectin/Cre to selectively express human sPRR in adipocytes (adi-HsPRR). Adi-HsPRR and control littermate (CTL) male and female mice were fed HF-diet for 20 weeks (N=8-15/group). Body weight was assessed weekly and body composition monthly. Blood pressure was measured by telemetry after 15 weeks of diet.

Adipose-derived human sPRR did not significantly elevate body weight or fat mass (Male: CTL.  18.3±1.0g; adi-HsPRR. 17.5±0.8g. Female: CTL.  15.6±1.5g; adi-HsPRR. 11.9±1.3g; pgt;0.05). Systolic blood pressure (SBP) significantly increased in HF-fed male and female mice. However, adipose-derived human sPRR did not further elevate SBP (24h SBP. Male: CTL. 136.0±1.7 mmHg; adi-HsPRR: 133.4±1.5 mmHg; Female: CTL. 131.9±2.8 mmHg; adi-HsPRR: 130.6±3.1 mmHg; pgt;0.05). Surprisingly, the anti-hypertensive effect of losartan (Los) to lower blood pressure was significantly reduced in adi-HsPRR male and female mice (Male: CTL. ΔSBP: -12.1±1.5 ΔmmHg; adi-HsPRR: -7.8±0.6 ΔmmHg; Female: CTL. ΔSBP: -13.4±1.1 ΔmmHg; adi-HsPRR: -5.7±2.3 ΔmmHg; plt;0.05). In 3T3-L1 cells, sPRR significantly increased phosphorylation of ERK1/2, which was not completely blunted by Los indicating that human sPRR could act as a partial agonist of AT1R or activate ERK1/2 independently of AT1R. Our data suggests that adipose-derived sPRR does not stimulate AT1R-mediated contractility, instead impairs Los efficacy.

This work was supported by the National Heart, Lung, and
Blood Institute Grant R01-HL-142969.