Deficiency of the soluble (pro)renin receptor attenuates Ang‐II induced hypertension

Abstract

Cleavage of the extra-cellular domain of the (pro)renin receptor (PRR) yields a soluble fragment (sPRR), that has been implicated in the pathogenesis of hypertension. We recently developed a novel mouse model with mutation in the cleavage site of the PRR using CRISPR/Cas9 such that sPRR is not generated. Since the gene encoding PRR is on the X-chromosome, male mice have markedly lower plasma sPRR levels (control: 21.5 ± 2.5 vs mutant: 0.2 ± 0.03 ng/ml, p<0.001) while female mice (being heterozygous) have roughly 40% reduction in plasma sPRR levels (control: 11.6 ± 1.6 vs mutant: 6.2 ± 1.0 ng/ml, p<0.01). In this study, we examined if deficiency of the sPRR in female mutant mice alters blood pressure (BP) in Ang-II induced hypertension. Unlike male mutant mice, female mutant mice had similar body weight compared to controls (control: 34.9 ± 2.3 vs mutant: 31.4 ± 1.8 g). Despite similar baseline BP, female mutant sPRR mice had an attenuated hypertensive response to 2 weeks of Ang-II infusion (400 ng/kg/min) (Figure 1) compared to controls. Female mutant sPRR mice also had enhanced urinary Na and K excretion compared to controls on day 2 and day 7 of Ang-II infusion (day 2: UNaV - control: 111.8 ± 19.4 vs mutant: 235.4 ± 24.3 μmol/day, p<0.01; UKV - control: 193.7 ± 44.6 vs mutant: 349 ± 39.4 μmol/day, p<0.05; day 7: UNaV - control: 120.5 ± 9.4 vs mutant: 166.6 ± 16.5 μmol/day, p<0.05; UKV - control: 177.6 ± 14.7 vs mutant: 246.2 ± 19.8 μmol/day, p<0.05;) with similar food intake, water intake and urine volume between the two groups. No differences were observed in urine albumin excretion (control: 28.1 ± 15.2 vs mutant: 24.1 ± 3.9 μg/day) while urinary excretion of kidney injury molecule-1 (KIM-1) tended to be lower in mutant mice compared to controls (control: 4.1 ± 1.7 vs mutant: 1.6 ± 0.5 ng/day). These results suggest that sPRR plays a role in Ang-II induced hypertension. Further studies are ongoing to determine the mechanisms by which sPRR might regulate BP in female mutant mice.