Olfactory receptor 78 regulates erythropoietin and cardiorespiratory responses to hypobaric hypoxia

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.