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The Brain, Not the Kidney, is the Source of Erythropoietin in Response to Hypoxic Hypoxia
Author(s) -
Allwood Melissa A,
Romanova Nadya,
Brunt Keith R,
Simpson Jeremy A
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.841.16
Subject(s) - erythropoietin , hypoxia (environmental) , erythropoiesis , medicine , regulator , kidney , cerebral hypoxia , immunology , endocrinology , biology , chemistry , oxygen , ischemia , anemia , biochemistry , organic chemistry , gene
Erythropoietin (EPO), the principle regulator of erythropoiesis, is central to our understanding of tissue hypoxia. For over a century, the kidney has been regarded as the primary site of EPO production. While multiple extra‐renal sources have been identified, their physiological significance remains largely uninvestigated. Further, studies investigating the source of EPO production use severe (non‐survivable) levels of hypoxia, despite that levels encountered in most pathophysiological states are mild to moderate. The assumption being that the response to less severe hypoxic stimuli is linearly scaled. Our objective was to investigate whole‐body EPO production in response to clinically‐relevant levels of hypoxia. We performed a multi‐organ, temporal analysis of EPO expression in response to moderate (F I O 2 = 0.15) and severe (F I O 2 = 0.09) hypoxic hypoxia. Using the Cre‐lox system, we proved that the brain, and not the kidney, was the sole responder to moderate hypoxia and the primary responder to severe. Thus, the erythropoietic response to hypoxia involves multiple tissues in a degree‐ and duration‐dependent manner with the brain as the first and primary site of EPO production. These data identify a critical shift in our understanding of oxygen carrying capacity in hypoxic hypoxia from peripheral to central regulation. Support or Funding Information This work was funded in part by grants from the Canadian Institutes of Health Research (JAS; Grant # MOP111159) and the Natural Sciences and Engineering Research Council of Canada (JAS). JAS is also a new investigator with the Heart and Stroke Foundation of Ontario.