Project Summary Premenopausal females have blood pressure that is ~10mmHg lower than that of males. We previously reported that an evolutionarily conserved olfactory receptor, OLFR558, is expressed in the kidney. We have now found that sex differences in blood pressure are absent in Olfr558 knockout (KO) mice, primarily due to increased blood pressure in females, along with a decreased diastolic pressure in males. In Aim 1, we will determine which OLFR558-expressing cell types are primarily responsible for the blood pressure phenotype in males and females. OLFR558 is expressed both in the vasculature and in the renal afferent arteriole (where renin is stored and secreted from); thus, we will examine both renin levels and vascular responses in male and female whole-animal KO mice. In addition, we will examine these same parameters, along with blood pressure by telemetry, in mice with tissue-specific Olfr558 rescue only in the vasculature, or, only in renin-expressing cells. In Aim 2, we will use gonadectomy in wild-type and KO mice to test the hypothesis that OLFR558 relies on gonadal signals to mediate sex differences. In parallel experiments we will use the four core genotype model, in which gonadal and chromosomal sex are separately inherited, to further interrogate this hypothesis. Finally, it is well-established that males have a higher incidence of hypertension than premenopausal females; this is true both in humans, and, in animal models of hypertension. In Aim 3, we will examine how OLFR558 influences sex differences in hypertension using two different hypertension models (Angiotensin II infusion, and, DOCA/Salt). In sum, these studies will reveal key insights into the function of an evolutionarily conserved OR which is required for sex differences in blood pressure.