The Role of Olfactory Receptor 558 in Blood Pressure Regulation and Aging

A recently published study from our lab found 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 across several species with females having lower BP by ~10mmHg. 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). Our previous study also reported that 3–4-month-old male KOs had decreased renin and Akr1b7 expression in the kidney, and lower plasma renin activity relative to male WT mice. On the other hand, 3-4-month-old female KOs displayed greater pulse wave velocity relative to female WT mice. In the current study, our aim was to investigate how these parameters change with aging, especially given that sex differences in blood pressure are lost with aging. Using BP telemetry, we find an elevation in blood pressure with aging in wildtype (WT) females (n=8, 12-13 mo) relative to young WT females (n=8, 5-6 mo) in MAP (Young:93.2±1 vs. Aged:105.9±1.1 mmHg, p <0.0001), SBP (Y:106.9±1 vs. A:118.4±1.2 mmHg, p <0.0001), and DBP (Y:78.8±1 vs. A:93.7±1 mmHg, p <0.0001). This difference is absent when comparing young (n=8, 5-6 mo) and aged (n=8, 12-13 mo) Olfr558 KO females for MAP (Young:98.9±1.2 vs. Aged:98.3±1.4 mmHg), SBP (Y:112.3±1.3 vs. A:112.2±1.4 mmHg), and DBP (Y:85.1±1 vs. A:84.0±1.2 mmHg). We hypothesize that Olfr558 is a key regulator of increased blood pressure with aging, especially in postmenopausal females. To further characterize this phenotype, renal Olfr558, renin, and Akr1b7 (a renin cell-specific marker) were measured by qPCR in aged mice (data presented as delta Ct normalized to a housekeeping gene). Further, plasma renin activity (PRA) was measured by ELISA, and aortic stiffness was assessed by pulse wave velocity (PWV). In aged mice (15-21-mo), male KOs (n=5) no longer exhibit decreased renal renin expression (WT: 1.4±0.2 vs KO: 1.4±0.1) or Akr1b7 (WT: 0.08±0.006 vs KO: 0.07±0.004), nor do they have lowered PRA (WT: 211±60 ng Ang-1/mL/hr vs KO: 158±17 ng Ang-1/mL/hr) relative to male WT mice (n=4). Aged female KOs continue to display increased PWV (m/s) relative to both aged female WT and aged male KO mice (aged KO F: 7.2±0.1 vs aged WT F: 4.9±0.5, p <0.05; aged KO M: 5.0±0.7, p <0.05; n=5). We also show that renal Olfr558 expression is similar between the sexes in young (4 mo, n=4) WT mice (M: 0.002±0.0003 vs F: 0.003±0.0003), while a sex difference emerges in aged (15-21 mo, n=4-5) mice with females exhibiting twice the amount of renal Olfr558 (M: 0.002±0.0003 vs F: 0.004±0.0003). Our findings demonstrate a possible role for Olfr558 in mediating age-related increases in blood pressure, particularly in postmenopausal females. 5R21AG081683-02 (JLP) This abstract was presented at the American Physiology Summit 2025 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.