Abstract 041: Renal-derived Human Sprr Increases Blood Pressure In Female Mice But Not In Male Mice

Abstract

The soluble prorenin receptor (sPRR) plays an important role in blood pressure regulation. In rodent models, sPRR contributes to Ang II production by increasing renin activity and systolic blood pressure (SBP). However, there is a gap of knowledge concerning the functional role of locally produced human sPRR from the kidney in blood pressure regulation. Therefore, we evaluated the role of renal-derived human sPRR in SBP control.Human sPRR-Myc-tag transgenic mice were bred with mice expressing Hoxb7/Cre to selectively express human sPRR in the collecting duct (RHsPRR). RHsPRR and control (CTL) male and female mice were fed a standard diet for 10 months (n=8-11/group). Body weight was examined weekly and SBP measured by radio-telemetry. Western blot analysis depicted the presence of human sPRR-Myc-tag (28 KDa) in the cortex and medulla of RHsPRR male mice which validated the humanized mouse model. Renal-derived human sPRR did not change body weight in male or female mice (M: CTL: 34±1, RHsPRR: 33±1 g; F: CTL: 28±1, RHsPRR: 30±1 g). Circulating sPRR was also unchanged in male and female mice (M: 3995±643 and 4342±500pg/ml, F: 3479±194 and 3948±238pg/ml). SBP increased significantly in female RHsPRR mice compared to CTL (F: 118.7±2 and 127.2±3 mmHg, P<0.05) but not in male mice (M: 123.8±2 and 119.9±6 mmHg). In female mice, renal-derived human sPRR increased significantly renal AT1R gene expression (F: 1.7±0.5 and 2.6±0.4 2 -ΔΔCT , P<0.05) and stimulated ERK1/2 (F: 0.3±0.0 and 0.6±0.1 AU, P<0.05) suggesting that human sPRR increases blood pressure in female mice likely via AT1R-ERK1/2 pathway activation. In contrast, in male mice, AT1R-ERK1/2 pathway was not up-regulated and renal ACE2 gene expression was significantly increased in RHsPRR males (M: 1.0±0.2 and 3.3±1.1 2 -ΔΔCT , P<0.05). Mechanistically, in male mice, our results indicated that the lack of activation of AT1R-ERK1/2 pathway combined with the increase of ACE2 could have prevented RHsPRR-induced increase in SBP. Together, our data highlighted the contribution of renal human sPRR to blood pressure control in a sex-dependent manner and a new mechanism of blood pressure control that involved the renin angiotensin system.