Renal‐derived human sPRR increases blood pressure in female but not male mice

Abstract

Previous studies showed that soluble prorenin receptor (sPRR) plays an important role in blood pressure regulation. In rodent models, sPRR contributes to AngII production by increasing renin activity and systolic blood pressure (SBP). Moreover, reducing sPRR release into plasma decreased blood pressure and attenuated angiotensin II (AngII) induced hypertension. However, there is a gap of knowledge concerning the functional role of locally produced sPRR from the kidney in blood pressure regulation. Additionally, the role of human sPRR in blood pressure regulation has not been delineated. Therefore, we evaluated the renal derived human sPRR role 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 and urine flow rate were examined and SBP measured by radiotelemetry. 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.Male mice have higher body weights than female mice but renal derived human sPRR did not influence body weights (M: 34.1±0.8 and 32.9±0.8g, F: 28.4±0.8 and 29.6±0.5g, P<0.05). Circulating sPRR was unchanged between 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). The SBP response to losartan, an AT1R antagonist, was unchanged in females but was impaired in males (M: ‐7.6±1.2 and ‐5.5±0.8 mmHg, F: ‐6.5±1.2 and ‐7.9±1.5 mmHg, P<0.05). Renal derived human sPRR significantly increased AT1R gene expression in females but not in males (M: 1.8±0.6 and 1.2±0.3 2‐ΔΔCT, F: 1.6±0.5 and 3.8±0.9 2‐ΔΔCT, P<0.05). Moreover, renal derived human sPRR decreased the gene expression of renin and angiotensinogen in female mice (Renin: 1.5±0.5 and 0.4±0.1 2‐ΔΔCT, Angiotensinogen: F: 0.9±0.1 and 0.6±0.1 2‐ΔΔCT, P<0.05) suggesting a negative feedback loop involving Angiotensin II‐AT1R pathway. These effects were not observed in males (Renin: 3.3±1.2 and 4.1±1.2 2‐ΔΔCT; Angiotensinogen: M: 1.4±0.4 and 1.4±0.4 2‐ΔΔCT).Overall, our data suggest that renal‐derived human sPRR increases blood pressure in female mice likely via the activation of renal AT1R expression. In contrast, renal‐derived human sPRR expression impaired the blood pressure response to Losartan in male mice. In conclusion, our data support renal derived human sPRR as a promising therapeutic target in hypertension in humans.