Differential HIF and NOS responses to acute anemia: defining organ-specific hemoglobin thresholds for tissue hypoxia
| Autor: | C. David Mazer, John G. Sled, R. Mark Henkelman, Albert K. Y. Tsui, Neville Chan, Lindsay S. Cahill, Gregory M. T. Hare, Keith M. Lee, Elaine Liu, Philip A. Marsden, Yu-Qing Zhou |
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| Rok vydání: | 2014 |
| Předmět: |
Monocarboxylic Acid Transporters
medicine.medical_specialty Nitric Oxide Synthase Type III Physiology Anemia Recombinant Fusion Proteins Muscle Proteins Mice Transgenic Nitric Oxide Synthase Type I Biology Kidney Severity of Illness Index Renal Circulation Hemoglobins Mice Luciferases Firefly Physiology (medical) Internal medicine Oxygen homeostasis Basic Helix-Loop-Helix Transcription Factors medicine Animals Humans Hypoxia Erythropoietin Hemodilution Hemodynamics Brain Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Disease Models Animal Endocrinology medicine.anatomical_structure Liver Hypoxia-inducible factors Cerebrovascular Circulation Renal blood flow Acute Disease Hemoglobin medicine.symptom Biomarkers medicine.drug |
| Zdroj: | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 307:R13-R25 |
| ISSN: | 1522-1490 0363-6119 |
| Popis: | Tissue hypoxia likely contributes to anemia-induced organ injury and mortality. Severe anemia activates hypoxia-inducible factor (HIF) signaling by hypoxic- and neuronal nitric oxide (NO) synthase- (nNOS) dependent mechanisms. However, organ-specific hemoglobin (Hb) thresholds for increased HIF expression have not been defined. To assess organ-specific Hb thresholds for tissue hypoxia, HIF-α (oxygen-dependent degradation domain, ODD) luciferase mice were hemodiluted to mild, moderate, or severe anemia corresponding to Hb levels of 90, 70, and 50 g/l, respectively. HIF luciferase reporter activity, HIF protein, and HIF-dependent RNA levels were assessed. In the brain, HIF-1α was paradoxically decreased at mild anemia, returned to baseline at moderate anemia, and then increased at severe anemia. Brain HIF-2α remained unchanged at all Hb levels. Both kidney HIF-1α and HIF-2α increased earlier (Hb ∼70–90 g/l) in response to anemia. Liver also exhibited an early HIF-α response. Carotid blood flow was increased early (Hb ∼70, g/l), but renal blood flow remained relatively constant, only increased at Hb of 50 g/l. Anemia increased nNOS (brain and kidney) and endothelia NOS (eNOS) (kidney) levels. Whereas anemia-induced increases in brain HIFα were nNOS-dependent, our current data demonstrate that increased renal HIFα was nNOS independent. HIF-dependent RNA levels increased linearly (∼10-fold) in the brain. However, renal HIF-RNA responses (MCT4, EPO) increased exponentially (∼100-fold). Plasma EPO levels increased near Hb threshold of 90 g/l, suggesting that the EPO response is sensitive. Collectively, these observations suggest that each organ expresses a different threshold for cellular HIF/NOS hypoxia responses. This knowledge may help define the mechanism(s) by which the brain and kidney maintain oxygen homeostasis during anemia. |
| Databáze: | OpenAIRE |
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