Investigating the Role of Olfactory Receptor 558 in Blood Pressure Regulation and Aging

Background: We previously reported that olfactory receptor 558 (Olfr558) is expressed in renin cells in the kidney, and in vascular smooth muscle (PMID: 38507492). Sex differences in normotensive blood pressure (BP)—with females having lower BP—are well-documented; however, we reported that they are absent in Olfr558 knockout (KO) mice for systolic (SBP), diastolic (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) vs male wildtypes (WT), while female KOs had increased pulse wave velocity (PWV) vs WT females. Here, we examined how these parameters change with aging, as sex differences in BP decline with age. Methods: We measured BP via telemetry and we quantified renal Olfr558, renin, and Akr1b7 expression by qPCR (delta Ct, arbitrary units (a.u.)), PRA by ELISA, and aortic stiffness via PWV. Results: In WT females, relatively older mice (12–13 mo, n=8) have increased BP compared to young WT (5–6 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 older vs young 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±1.2 mmHg). 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.), Akr1b7 (WT: 0.08±0.006 vs. KO: 0.07±0.004 a.u.), or PRA (WT: 211±60 vs. KO: 158±17 ng Ang-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<0.05). Finally, renal Olfr558 expression (a.u., qPCR) is higher in young WT females (4 mo, n=8–9) vs. young males (F: 0.011±0.0007 vs. M: 0.007±0.0004 a.u., p<0.05), with the difference widening with age (15–21 mo, n=4–5; F: 0.016±0.0015 vs. M: 0.007±0.0004 a.u., p<0.0001). Cardiac Olfr558 is also greater in young WT females (4 mo, n=5; F: 0.0001±3.25×10-6 vs. M: 0.0001±0.00001 a.u., p<0.01) and remains elevated in aged females (15–21 mo, n=4–5; F: 0.00009±0.000004 vs. M: 0.00007±0.000002 a.u., p<0.05), despite overall age-related decline. Conclusion: Our findings suggest Olfr558 may mediate age-associated BP increases, particularly in postmenopausal females. Funding: NIDDK Support - NIDDK Support, NIDDK Support