Uncovering a sex‐specific role for olfactory receptor 558 (Olfr558) in blood pressure regulation

Abstract

Olfactory receptors are primarily studied in the nose; but are also expressed and play pivotal roles in non‐olfactory tissues as ecnomotopic receptors. We find that olfactory receptor 558 (Olfr558) is expressed in vascular smooth muscle cells in the kidney, including the renal afferent and efferent arterioles. We developed Olfr558 whole‐body knockout (KO) mice to test the hypothesis that Olfr558 plays a role in blood pressure (BP) regulation. Olfr558 wild‐type (WT) vs. KO (males and females) exhibited no genotypic differences in body weight, kidney weight/body weight, heart weight/body weight, glomerular filtration rate, or blood values (electrolytes, glucose, blood urea nitrogen, creatinine, and hemoglobin). However, Olfr558 KO males had lower diastolic blood pressure (DBP) (81.1±1.6 mmHg, n=9, p=0.009) than WT males (89.1±2.2 mmHg, n=7) during the light cycle (telemetry) without a change in mean arterial (MAP) or systolic blood pressure (SBP). In contrast, Olfr558 KO females had increased MAP (KO: 95.0±1.7 mmHg, WT: 89.0±0.9 mmHg, p=0.003), SBP (KO: 108.0±1.7 mmHg, WT: 102.1±1.4 mmHg, p=0.02), and DBP (KO: 81.6±1.6 mmHg, WT: 75.0±0.9 mmHg, p=0.003) during the light cycle (n=8 for WT and KO). A similar trend was observed during the dark cycle. These data suggest that Olfr558 regulates BP in a sex‐specific manner.To determine the mechanisms underlying the sexually dimorphic effect of Olfr558 on BP regulation, we are examining renin signaling and vascular tone. In males, kidney renin mRNA levels were significantly decreased in Olfr558 KO (0.43±0.04, n=12, p=0.001 vs WT 1±0.14, n=11). Akr1b7 (renin cell marker) mRNA was also reduced in male KO (0.5±0.06, n=12, p=0.002, vs WT 1±0.09, n=10). We then evaluated the % of renin positive to total glomeruli and found that it was reduced in male KO (29.0±0.95, p=0.004, vs WT 43.2±1.88; n=8). We also found that plasma renin activity (PRA) was dramatically decreased in male KO (200.8±20.5, n=11, p=0.001) than WT (401.9±15.2, n=10). These results suggest that Olfr558 regulates BP in males at least in part via renin. In females, there were no differences in renin or Akr1b7 mRNA, nor in the % of renin positive glomeruli, nor PRA. These results suggest that, in females, Olfr558 modulates BP independent of renin. Studies of ex vivo vascular reactivity in males show that aortic rings exhibited less constriction to Phenylephrine (PE) in KO vs WT, which could contribute to the hypotension seen in these mice. In contrast, constriction to KCl and relaxation to Acetylcholine (ACh) and sodium nitroprusside (SNP) showed no genotypic difference. KO mesentery exhibited more relaxation to SNP, but not ACh, and similar constriction to KCl and PE as WT. In females, KO aortic rings exhibited more constriction to KCl, but not PE, and similar relaxation to ACh and SNP as WT. However, mesentery showed no genotypic difference in constriction to KCl and PE, relaxation to ACh and SNP. Thus, our findings suggest that the hypotension seen in Olfr558 KO males is likely contributed to both by decreased renin and by changes in vascular reactivity, whereas the origin of hypertension seen in Olfr558 KO females is still an area of active investigation.