Red blood cell antibody-induced anemia causes differential degrees of tissue hypoxia in kidney and brain

  • Nikhil Mistry
    Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
  • C. David Mazer
    Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
  • John G. Sled
    Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Alan H. Lazarus
    Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
  • Lindsay S. Cahill
    Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Max Solish
    Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
  • Yu-Qing Zhou
    Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Ontario, Canada
  • Nadya Romanova
    Department of Human Health and Nutritional Sciences and Cardiovascular Research Group, University of Guelph, Guelph, Ontario, Canada
  • Alexander G. M. Hare
    Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
  • Allan Doctor
    Department of Pediatrics, Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri
  • Joseph A. Fisher
    Department of Physiology, University of Toronto, Toronto, Ontario, Canada
  • Keith R. Brunt
    Department of Pharmacology, Dalhousie University, Saint John, New Brunswick, Canada
  • Jeremy A. Simpson
    Department of Human Health and Nutritional Sciences and Cardiovascular Research Group, University of Guelph, Guelph, Ontario, Canada
  • Gregory M. T. Hare
    Department of Anesthesia, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

説明

<jats:p> Moderate anemia is associated with increased mortality and morbidity, including acute kidney injury (AKI), in surgical patients. A red blood cell (RBC)-specific antibody model was utilized to determine whether moderate subacute anemia could result in tissue hypoxia as a potential mechanism of injury. Cardiovascular and hypoxic cellular responses were measured in transgenic mice capable of expressing hypoxia-inducible factor-1α (HIF-1α)/luciferase activity in vivo. Antibody-mediated anemia was associated with mild intravascular hemolysis (6 h) and splenic RBC sequestration ( day 4), resulting in a nadir hemoglobin concentration of 89 ± 13 g/l on day 4. At this time point, renal tissue oxygen tension (P<jats:sub>t</jats:sub>O<jats:sub>2</jats:sub>) was decreased in anemic mice relative to controls (13.1 ± 4.3 vs. 20.8 ± 3.7 mmHg, P < 0.001). Renal tissue hypoxia was associated with an increase in HIF/luciferase expression in vivo ( P = 0.04) and a 20-fold relative increase in renal erythropoietin mRNA transcription ( P < 0.001) but no increase in renal blood flow ( P = 0.67). By contrast, brain P<jats:sub>t</jats:sub>O<jats:sub>2</jats:sub> was maintained in anemic mice relative to controls (22.7 ± 5.2 vs. 23.4 ± 9.8 mmHg, P = 0.59) in part because of an increase in internal carotid artery blood flow (80%, P < 0.001) and preserved cerebrovascular reactivity. Despite these adaptive changes, an increase in brain HIF-dependent mRNA levels was observed (erythropoietin: P < 0.001; heme oxygenase-1: P = 0.01), providing evidence for subtle cerebral tissue hypoxia in anemic mice. These data demonstrate that moderate subacute anemia causes significant renal tissue hypoxia, whereas adaptive cerebrovascular responses limit the degree of cerebral tissue hypoxia. Further studies are required to assess whether hypoxia is a mechanism for acute kidney injury associated with anemia. </jats:p>

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