High‐altitude hypoxia decreases plasma erythropoietin soluble receptor (sEpoR) concentration in humans

Abstract

RationaleErythropoietin (Epo) is the main erythropoietic hormone, and its expression increases several fold under hypoxic conditions. Epo acts on membrane Epo receptor (EpoR) in the bone marrow and promotes the survival, proliferation, and differentiation of erythroid progenitors to increase red blood cell (RBC) production. Following acute hypoxic exposure, circulating Epo increases within 2h, reaching maximal values around 48h, and decline afterwards despite continuous hypoxia.Recently, a soluble form of the Epo receptor (sEpoR), has been suggested to modulate the action of Epo. By binding the hormone, sEpoR reduces its effective plasma concentration. Conversely, decreasing sEpoR concentration increases free circulating Epo and therefore increase its availability to erythropoietic progenitors. So far, studies on the receptor have shown that intermittent hypoxia exposure decreases sEpoR expression and circulating concentration. However, whether changes in plasma sEpoR concentration occur during continuous hypoxia, such as during high‐altitude (HA) exposure, and what is the relationship of circulating sEpoR with Epo and erythropoiesis is yet unknown. Therefore, the aim of this study is to characterize the concentration time‐course profile of plasma sEpoR, Epo, and reticulocyte count (RC), in healthy lowlanders at sea‐level and during the first four days at HA.MethodsTwenty‐two male sea‐level residents, in the age range from 18 to 65 years, were recruited for the study to travel from Lima (150m) to Cerro de Pasco (4340m, BP = 456 mmHg). Participants read and signed an informed consent, and underwent clinical examination including a general health questionnaire and Lake Louise Score. SpO2, heart rate, systolic and diastolic blood pressure, and hematocrit were evaluated. The protocol was designed to span 72h of high‐altitude exposure with measurements every 12h, starting 12h before ascent. Venous blood samples were collected to quantify Epo and sEpoR, and to determine the percentage of change of reticulocyte count (RC) at every time point. Epo and sEpoR levels were quantified in serum and plasma samples, respectively, using ELISA immunosorbent specific kits (USCN Life Science Inc., Houston).ResultsHypoxia progressively decreased plasma sEpoR down by 14% at 48h, and remained below its baseline until 72h. In parallel, and as expected, Epo levels increased during the first hours of hypoxia, reaching a peak (13‐fold) at 48h, and then progressively decreased 7‐fold by 72h. RC increased significantly from 24h, and continued to increase until 72h without reaching a plateau.ConclusionOur results show that continuous HA hypoxia decreases plasma sEpoR concentration, and that RC increases linearly until the end of hypoxic exposure despite decreasing Epo levels. This finding suggests a potential role of sEpoR on continuous erythropoietic drive and sustained RBCs production.Support or Funding InformationFunding: Research supported by a Wellcome Trust grant (107544/Z/15/Z) to FC. VillafuerteThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.