Sex differences in soluble (pro)renin receptor regulation of blood pressure

Abstract

Background: 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 mutant 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 mutant 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 sex differences in the mechanisms regulating blood pressure (BP) between male and female mutant sPRR mice and their littermate controls following angiotensin-II induced hypertension and DOCA-salt hypertension. Methods: Male and female control and mutant sPRR mice aged 3-4 months of age were treated with angiotensin-II (Ang-II, 400 ng/kg/min, n= 6-8/group)) for 2 weeks or DOCA (50 mg/kg, n=5-6/group) and saline for 3 weeks. BP was monitored by radio-telemetry. Metabolic balance studies were performed during course of Ang-II infusion or at the end of DOCA-salt treatment. Results: Compared to controls, male mutant sPRR mice had lower baseline blood pressure (systolic - 118 ± 4 vs control: 125 ± 3 mm of Hg) as well as attenuated hypertensive response to Ang-II infusion (systolic day 7: 122 ± 5 vs control: 150 ± 6; day 14: 128 ± 7 vs control: 158 ± 4 mm Hg) and DOCA-salt treatment (systolic day 17: 132 ± 5 vs control: 141 ± 2 mm Hg). In contrast, female control and mutant sPRR mice had similar BP at baseline (systolic 112 ± 4 vs control: 113 ± 6 mm Hg) and following DOCA-salt treatment (systolic day 17: 141 ± 9 vs control: 139 ± 11 mmHg). However, female mutant sPRR mice had an attenuated hypertensive response to Ang-II infusion compared to female controls (systolic day 7: 116 ± 17 vs controls:134 ± 16; day 14:126 ± 20 vs control:149 ± 20 mm Hg). Male control and mutant sPRR mice had no differences in urinary Na+ or K+ excretion with Ang-II infusion while female mutant sPRR mice had enhanced urinary Na and K excretion compared to controls on day 2 and day 7 of Ang-II infusion. Both male and female mutant sPRR mice had attenuated vasoconstrictor response to Ang-II in isolated mesenteric arteries despite similar Ang-II receptor expression. We are currently examining differences in renin angiotensin aldosterone system markers between male and female control and mutant sPRR mice following Ang-II/DOCA-salt hypertension. Conclusion: These results suggest that sPRR plays a role in Ang-II induced hypertension in male and female mice through modulation of urinary Na+/K+ excretion and vascular reactivity. sPRR is also involved in regulating BP with DOCA-salt treatment in male but not female mice. NHLBI This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.