Absence of Erythropoietin and Cardio‐respiratory Responses to Hypobaric Hypoxia in Olfactory Receptor 78 Null mice

Abstract

Hypobaric hypoxia (HH) evokes a series of physiological adaptations, including carotid body (CB)–dependent ventilatory acclimatization to hypoxia (VAH), elevated blood pressure (BP), and stimulation of erythropoietin (Epo) gene in the kidney. Olfactory receptor 78 (Olfr78) is a G‐protein coupled receptor that has been implicated in CB response to acute hypoxia. Given that both CB and kidney express Olfr78, we tested the hypothesis that Olfr78 plays a role in the cardio‐respiratory and renal Epo gene responses to HH. Studies were performed on wild type (WT) and Olfr78 null mice reared in room air (control) or exposed to 18h of HH (0.4 atmospheres). HH treated WT exhibited: 1) VAH manifested as increased baseline breathing, and enhanced hypoxic ventilatory response (HVR; 12% O2); 2) elevated BP and plasma norepinephrine levels; and 3) increased baseline CB sensory nerve activity and augmented CB sensory nerve response to subsequent acute hypoxia‐ all these responses to HH are either markedly attenuated or absent in Olfr78 null mice. 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 suggest a role for Olfr78 in physiological adaptations to HH experienced at high altitude