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Deficiency of the soluble (pro)renin receptor attenuates Ang‐II induced hypertension
Author(s) -
Ramkumar Nirupama,
Peterson Caitlin,
Stuart Deborah,
Wheatley Will,
Kohan Donald
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03254
Subject(s) - mutant , medicine , endocrinology , plasma renin activity , pathogenesis , receptor , chemistry , excretion , renin–angiotensin system , gene , blood pressure , biochemistry
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.