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

Abstract

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 (PO) 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 PO 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.

Moderate and severe hypoxia elicit divergent effects on cardiovascular function and physiological rhythms

“…; Mistry et al . ). Expression of EPO, nitric oxide synthase (NOS) and monocarboxylate transporter 4 are all differentially activated between mild, moderate and severe anaemia in an organ‐specific manner (Tsui et al .…”

“…The time profile of HIF-1α expression also appears to be organ-specific and differs between moderate and severe hypoxia (Stroka et al 2001). This organ-specific transcriptional response to hypoxia is also seen in anaemia, where, in response to mild, moderate and severe anaemia, heterogeneous expression of HIF-1α occurs in the brain, kidney and liver (Tsui et al 2014;Mistry et al 2018). These patterns are not necessarily reflected in the expression of HIF downstream targets [e.g.…”

“…; Mistry et al . ). These patterns are not necessarily reflected in the expression of HIF downstream targets [e.g.…”

A mathematical model of cerebral blood flow control in anaemia and hypoxia

“…; Mistry et al . ). Although the model is compatible with the hypothesis of CBF regulated according to , it does not differentiate between as a sensed variable or a correlated result of alternate mechanisms of CBF regulation.…”

“…; Mistry et al . ) and recent evidence for a central respiratory oxygen sensor (Gourine & Funk, ). The importance of maintaining brain oxygen tension and evidence of alternate central and peripheral mechanisms for regulating CBF suggest that multiple co‐operative oxygen sensing mechanisms contribute.…”