Olfactory receptor 558 (OLFR558) is an evolutionarily conserved olfactory receptor whose role oustide the olfactory epithelium is unknown. We used RNAScope to show that Olfr558 is expressed in vascular smooth muscle, including the renal afferent arteriole; the human ortholog (OR51E1) exhibits a similar pattern of expression in published RNASeq data. We then measured blood pressure (BP) in Olfr558 wild-type (WT) and knockout (KO) mice via telemetry. It is well-established that males (M) have a higher BP than females (F). We measured systolic (SBP), diastolic (DBP), and mean arterial pressure (MAP) using n=7-9 per sex and per genotype. We find that, as expected, Olfr558WT M have higher BP than F, 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=0.0025), and DBP (M: 89±2 vs. F:75±01mmHg, p<0.0001). However, sex differences in BP are absent when comparing M vs F 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). To explore this finding, we analyzed kidney renin expression by qPCR and plasma renin activity (PRA) by ELISA, and measured pulse wave velocity in females. In male KOs (n=10-12), kidney renin mRNA decreased (0.4±0.1 vs WT: 1±0.1 p=0.001), as did PRA (201±21 vs WT: 402±15, p=0.001); both kidney renin mRNA and PRA were unchanged in female KOs. However, females exhibited increased pulse wave velocity (PWV; KO: 4.6±0.4 vs WT: 3.2±0.2 m/s, p=0.0069, n=8-11). The human ortholog of OLFR558, OR51E1, was previously identified as a locus associated with DBP, and we also have identified an OR51E1 variant with a sex-specific effect. In sum, an evolutionarily conserved olfactory receptor is required for sex differences in BP.

Funding: R56DK107726, R21AG081683