Abstract: SA-PO774
Olfactory Receptor 558 (Olfr558) Is Required for Sex Differences in Blood Pressure
Session Information
- Hypertension and CVD: Mechanisms
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1503 Hypertension and CVD: Mechanisms
Authors
- Xu, Jiaojiao, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
- Choi, Rira, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
- Warren, Helen R., Queen Mary University of London Barts and The London School of Medicine and Dentistry, London, London, United Kingdom
- Gupta, Kunal, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
- Santhanam, Lakshmi, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
- Pluznick, Jennifer L., Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Background
Olfactory receptor 558 (Olfr558) is expressed in the kidney where its functional role is unknown.
Methods
Olfr558 was localized using RNAScope. Systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP) was measured in whole-body Olfr558 wild-type (WT) and knockout (KO) via telemetry. Expression was analyzed by qPCR, plasma renin activity (PRA) was measured by ELISA, and vasoreactivity was examined ex vivo by wire myography (responses to potassium chloride (KCl), phenylephrine (PE), acetylcholine (Ach), and sodium nitroprusside (SNP) in aortic and mesenterics rings). In females, pulse wave velocity (PWV) and tensile testing were performed. Using UK Biobank data (N~450k), we performed genetic analyses of DBP, testing for sex-interaction effects.
Results
Olfr558 localizes to renal vascular smooth muscle cells, including the renal afferent arteriole. It is known that males have a higher BP than premenopausal females in both humans and mice; indeed, we find that Olfr558 WT males (M) had a higher BP than females (F, n=7-9 per group), including MAP (M:101.0±1.6 vs. F:89.0±0.9 mmHg, p<0.0001), SBP (M:113±2 vs. F:102±1mmHg, p=0.003), and DBP (M: 89±2 vs. F:75±01mmHg, p<0.0001). These sex differences in BP were absent in Olfr558 KO (MAP M: 96±2 vs. F: 95±1mmHg; SBP M: 110±2 vs. F: 108±2mmHg; DBP M: 81±2 vs. F: 82±2mmHg). However, other sex differences (body weight) are intact in KO, and KO males and females are fertile.
In male KOs (n=10-12), kidney renin mRNA was decreased (0.4±0.1 vs WT: 1±0.1 p=0.001), as was PRA (201±21 vs WT: 402±15, p=0.001); these parameters were unchanged in female KOs. Male KO aortic rings exhibited less constriction to PE, male KO mesenterics exhibited more relaxation to SNP, and female KO aortic rings exhibited more constriction to KCl. KO females have increased PWV (KO: 4.6±0.4 vs WT: 3.2±0.2 m/s, p=0.007, n=8-11), but no changes in tensile testing. The OR51E1 (the human ortholog of Olfr558) gene region was recently reported for association with DBP (PMID 30224653). Our UK Biobank analyses demonstrate a sex-specific effect for the lead variant rs17224476, with effects on DBP differing significantly (p=0.01) between men vs women.
Conclusion
Olfr558 is required for sex differences in BP in mice. Olfr558 regulates BP in males via renin and vascular reactivity, but via arterial stiffness in females.
Funding
- Other NIH Support