Investigating Olfactory Receptor 558 (Olfr558) mediated sex differences in blood pressure regulation and aging

We previously reported that Olfactory Receptor 558 (Olfr558) is expressed in renin-positive cells in the kidney, as well as in vascular smooth muscle cells (PMID: 38507492). Sex differences in normotensive blood pressure (BP) have been well-documented with females having lower BP. Using BP telemetry, we reported that sex differences are absent in Olfr558 knockout (KO) mice for systolic BP (SBP), diastolic BP (DBP) and mean arterial pressure (MAP). Additionally, 3–4-month-old male KOs had reduced renal renin and Akr1b7 expression and lower plasma renin activity (PRA) than male wildtypes (WT), while female KOs had increased pulse wave velocity (PWV) compared to WT females. In the aged, blood pressure increases in both sexes such that females no longer have lower blood pressure than males. In the current study, our aim was to investigate how Olfr558 expression changes with aging, and, how the KO phenotype changes with aging. We measured BP via telemetry and quantified renal Olfr558, renin, and Akr1b7 expression by qPCR (delta Ct, arbitrary units (a.u.)), PRA by ELISA, and aortic stiffness via PWV. In WT mice, young females (5-6 mo, n=8) have lower BP compared to relatively older females (12–13 mo, n=8): MAP (93.2±1 vs. 105.9±1.1 mmHg, p< 0.0001), SBP (106.9±1 vs. 118.4±1.2 mmHg, p< 0.0001), and DBP (78.8±1 vs. 93.7±1 mmHg, p< 0.0001). This increase is absent in young vs older KO females (n=8): MAP (98.9±1.2 vs. 98.3±1.4 mmHg), SBP (112.3±1.3 vs. 112.2±1.4 mmHg), and DBP (85.1±1 vs. 84.0±1.2mmHg). In aged mice (15–21 mo), male KOs (n=5) no longer differ from WT (n=4) in renin (WT: 1.4±0.2 vs. KO: 1.4±0.1 a.u. by qPCR), Akr1b7 (WT: 0.08±0.006 vs. KO: 0.07±0.004 a.u. by qPCR), or PRA (WT: 211±60 vs. KO: 158±17 ngAng-1/mL/hr). In contrast, aged female KOs (n=5) maintain elevated PWV compared to aged WT females (n=6) and aged KO males (7.2±0.1 vs. 4.9±0.5 and 5.0±0.7 m/s, p< 0.0001 and p< 0.001). Finally, renal Olfr558 expression (a.u., qPCR) is higher in young WT females relative to males (4-mo, n=10; F: 0.011±0.003 vs. M:0.007±0.002 a.u., p< 0.001), with the difference widening with age (15+mo, n=4-6; F: 0.016±0.002 vs. M:0.008±0.002 a.u., p< 0.0001). Cardiac Olfr558 is also greater in young WT females vs young WT males (4-mo, n=5-6; F:0.00014±0.00001 vs. M: 0.0009±0.00001 a.u., p< 0.01) but this sex difference is lost with age, as older females exhibit a decline in cardiac Olfr558 expression relative to younger females (15+mo, n=4–6; F: 0.00008±0.000004 vs. M: 0.00007±0.000005 vs 4-mo F: 0. 00014±0.00001 a.u., p< 0.01 and p< 0.001). Our findings suggest Olfr558 may mediate age-associated BP increases, particularly in postmenopausal females, and changes in renal and/or cardiac Olfr558 expression may help to drive this phenotype. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.