Sci STKE 2007: cm8, 2007

Sci STKE 2007: cm8, 2007. was maintained in anemic mice relative to controls (22.7??5.2 vs. 23.4??9.8 mmHg, = 0.59) in part because of an increase in internal carotid artery blood flow (80%, 0.001) and preserved cerebrovascular reactivity. Despite these adaptive changes, an increase in brain HIF-dependent mRNA levels was observed (erythropoietin: 0.001; heme oxygenase-1: = 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. 0.05} (28). A clearer understanding of the potential mechanisms by which this pattern of injury occurs may be gained by reviewing the well-characterized adaptive physiological responses to acute and chronic anemia (3, 29, 41, 42). The cardiovascular adaptations include an increase in cardiac output and a preferential redirection of blood flow to vital organs with high metabolic oxygen requirements, {including the brain and heart N-Desethyl Sunitinib (3,|including the heart and brain (3,} 32, 41C44). By contrast, no or limited increases in renal blood flow are observed during acute N-Desethyl Sunitinib hemodilution (15, 42), leading to earlier and more severe renal tissue hypoxia (5, 38), and an increase in the magnitude of N-Desethyl Sunitinib hypoxia signaling responses, including stabilization of the transcription factor hypoxia-inducible factor- (HIF-) (42, 43). This pattern of organ perfusion during anemia may explain why the kidney is more susceptible to tissue hypoxia and injury relative to the brain. This background led us to assess the impact of moderate subacute anemia on oxygen delivery to the kidney and brain in an animal model. {This model approximates the degree and time course of anemia in perioperative patients.|This model approximates the time and degree course of anemia in perioperative patients.} We want to test the overarching hypothesis that moderate subacute anemia results in tissue hypoxia. We were also interested in determining whether the level of anemia-induced tissue hypoxia was different between the kidney and the brain. To test this hypothesis, we utilized a novel model of subacute anemia induced by a red blood cell (RBC)-specific antibody (TER119) (4, 48). {As previously described,|As described previously,} TER119 is a monoclonal antibody specific to the glycophorin-A complex on the surface of RBC. Intravenous administration of this antibody induces a moderate degree anemia over a span of days, resulting in a subacute anemia (4, 19). Real-time cellular adaptation to anemia was assessed with a transgenic mouse ubiquitously expressing a luciferase reporter gene fused to the oxygen degradation-dependent (ODD) region of HIF-1 (33). {We also characterized the cardiovascular and HIF-dependent mRNA responses to anemia-induced tissue hypoxia in the kidney and brain.|We also characterized the cardiovascular and HIF-dependent mRNA responses to anemia-induced tissue hypoxia in the brain and kidney.} {MATERIALS AND METHODS Animals.|METHODS and MATERIALS Animals.} {Animal protocols were reviewed and approved by the Animal Care Committees at St.|Animal protocols were approved and reviewed by the Animal Care Committees at St.} Michaels Hospital and at The Centre for Phenogenomics and conducted in compliance with the Canadian Council on Animal Care and ARRIVE guidelines. HIF-ODD luciferase mice were purchased and bred in house [FVB.129S6-= 124, anemia: = 138, untreated: = 8). In addition, a magnetic resonance anatomic assessment was performed in three wild-type mice. For all experiments, the mean weights were comparable between groups (control: 26.4??2.4 g; anemia: 26.5??2.4 g; untreated: 26.9??1.5 g; = 0.86). {Animals had access to food and water ad libitum in a pathogen-free facility with a 12:12-h light-dark cycle.|Animals had access to water and food ad libitum in a pathogen-free facility with a 12:12-h light-dark cycle.} All experiments were conducted during the light cycle. As aligned with previous protocols, spontaneously breathing mice were anesthetized with 2% (vol/vol) isoflurane in 21% O2 at a flow rate of 2 l/min via nosecone for all experiments, except for experiments following the ultrasound biomicroscopy protocols that utilized 1.5% isoflurane. In addition, core body temperature was monitored by rectal probe and maintained by a heat pad between 36 and 37C. Hb concentrations were measured by a Hemocue Hb201+ analyzer (Radiometer, Angelholm, Sweden) from 10-l blood samples collected via tail nick. Antibody-induced FGF19 anemia. RBC-specific antibody (TER119) or isotype control (Rat IgG2) was administered to anesthetized mice via tail vein (1 g/g body weight; BioXCell, West Lebanon, NH). {Stock aliquots of TER119 or rat IgG2 were stored at|Stock aliquots of rat or TER119 IgG2 were stored at} ?{80C and diluted with saline.|diluted and 80C with saline.} Degree of anemia induced by RBC-specific antibody. Hb values were assessed over a 14-day period in mice injected with control antibody (= 11), RBC-specific antibody (= 16), and a subgroup of mice reinjected with a second dose of antibody at the time point (control: = 6; anemia: = 6). Plasma hemoglobin, spleen, and liver weight. Blood was collected from the abdominal aorta of control (= 56) and anemic.