title: Suppression of erythropoiesis by dietary nitrate.
abstract: In mammals, hypoxia-triggered erythropoietin release increases red blood cell mass to meet tissue oxygen demands. Using male Wistar rats, we unmask a previously unrecognized regulatory pathway of erythropoiesis involving suppressor control by the NO metabolite and ubiquitous dietary component nitrate. We find that circulating hemoglobin levels are modulated by nitrate at concentrations achievable by dietary intervention under normoxic and hypoxic conditions; a moderate dose of nitrate administered via the drinking water (7 mg NaNO3/kg body weight/d) lowered hemoglobin concentration and hematocrit after 6 d compared with nonsupplemented/NaCl-supplemented controls. The underlying mechanism is suppression of hepatic erythropoietin expression associated with the downregulation of tissue hypoxia markers, suggesting increased pO2. At higher nitrate doses, however, a partial reversal of this effect occurred; this was accompanied by increased renal erythropoietin expression and stabilization of hypoxia-inducible factors, likely brought about by the relative anemia. Thus, hepatic and renal hypoxia-sensing pathways act in concert to modulate hemoglobin in response to nitrate, converging at an optimal minimal hemoglobin concentration appropriate to the environmental/physiologic situation. Suppression of hepatic erythropoietin expression by nitrate may thus act to decrease blood viscosity while matching oxygen supply to demand, whereas renal oxygen sensing could act as a brake, averting a potentially detrimental fall in hematocrit.
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Ashmore
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Colin E
authors.initials: CE
authors.lastname: Evans
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Branco-Price
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
authors.affiliation: *Department of Physiology, Development, and Neuroscience and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom; and Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, United Kingdom ajm267@cam.ac.uk.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murray
mesh_terms: D000818:Animals; D019587:Dietary Supplements; D000068817:Epoetin Alfa; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009566:Nitrates / Q000008:administration & dosage* / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D006454:Hemoglobins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009566:Nitrates; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; D010100:Oxygen
keywords: hypoxia; kidney; oxygen sensing