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

Gertrude Arthur¹, Audrey Poupeau¹, Alexis Taylor², Kellea Nichols¹, Jacqueline
Leachman¹, Terry Hinds¹, Analia Loria¹, Jeffrey Osborn², Frederique Yiannikouris¹

¹Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536

²Department of Biology, University of Kentucky, Lexington, KY 40536

Soluble prorenin receptor (sPRR) plays an important role in regulating blood pressure
(BP). In rodent models, sPRR contributes to Ang II production by increasing renin activity
and systolic blood pressure (SBP). However, there is a gap in knowledge concerning the
functional role of locally produced human sPRR from the kidney in BP regulation.
Therefore, we evaluated the role of renal-derived human sPRR in SBP control. The
human sPRR-Myc-tag transgenic mice were bred with Hoxb7/Cre mice to express human
sPRR in the collecting duct (RHsPRR). The RHsPRR and control (CTL) male and female
mice were fed a standard diet for 10 months (n=8-11/group), and body weight was
examined weekly and SBP measured by radiotelemetry. Western blot analysis depicted
human sPRR-Myc-tag presence in the kidney of RHsPRR mice, validating the humanized
mouse model. The RHsPRR 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), and circulating sPRR was also
unchanged (M: 3995±643 and 4342±500pg/ml, F: 3479±194 and 3948±238pg/ml). SBP
increased significantly in the 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 the
female mice, RHsPRR increased 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 BP in female mice likely via AT1R-ERK1/2 pathway
activation. In contrast, in male mice, the AT1R-ERK1/2 pathway was not up-regulated,
and renal ACE2 gene expression was increased in RHsPRR males (M: 1.0±0.2 and
3.3±1.1 2-ΔΔCT, P<0.05). ACE2 upregulation combined with a lack of AT1R-ERK1/2
pathway activation could have prevented increased SBP in males. Together, our data
highlight the contribution of RHsPRR to BP control in a sex-dependent manner and
provide a new mechanism of BP control that involves sPRR and the renin-angiotensin
system.