Olfactory receptor (Olfr) 78 is expressed in the carotid bodies (CB) and participates in CB responses to acute
hypoxia. Olfr78 is also expressed in the kidney, which is a major site of
erythropoietin (Epo) production by
hypoxia. The present study examined the role of Olfr78 in cardiorespiratory and renal Epo gene responses to hypobaric
hypoxia (HH), simulating low O2 condition experienced at high altitude. Studies were performed on adult, male wild-type (WT) and Olfr78 null mice treated with 18 h of HH (0.4 atmospheres). HH-treated WT mice exhibited increased baseline breathing, augmented hypoxic ventilatory response, elevated blood pressure, and plasma
norepinephrine (NE) levels. These effects were associated with increased baseline CB sensory nerve activity and augmented CB sensory nerve response to subsequent acute
hypoxia. In contrast, HH-treated Olfr78 null mice showed an absence of cardiorespiratory and CB sensory nerve responses, suggesting impaired CB-dependent cardiorespiratory adaptations. WT mice responded to HH with activation of the renal Epo gene expression and elevated plasma Epo levels, and these effects were attenuated or absent in Olfr78 null mice. The attenuated Epo activation by HH was accompanied with markedly reduced
hypoxia-inducible factor (HIF)-2α
protein and reduced activation of HIF-2 target gene Sod-1 in Olfr78 null mice, suggesting impaired transcriptional activation of HIF-2 contributes to attenuated Epo responses to HH. These results demonstrate a hitherto uncharacterized role for Olfr78 in cardiorespiratory adaptations and renal Epo gene activation by HH such as that experienced at high altitude.NEW & NOTEWORTHY In this study, we delineated a previously uncharacterized role for
olfactory receptor 78 (Olfr78), a
G-protein-coupled receptor in regulation of
erythropoietin and cardiorespiratory responses to hypobaric
hypoxia. Our results demonstrate a striking loss of cardiorespiratory adaptations accompanied by an equally striking absence of carotid body sensory nerve responses to hypobaric
hypoxia in Olfr78 null mice. We further demonstrate a hitherto uncharacterized role for Olfr78 in
erythropoietin activation by hypobaric
hypoxia.