| Autor: |
Albert K. Y. Tsui, Marsden, Philip A., Mazer, C. David, Sled, John G., Lee, Keith M., Henkelman, R. Mark, Cahill, Lindsay S., Yu-Qing Zhou, Neville Chan, Elaine Liu, Hare, Gregory M. T. |
| Předmět: |
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| Zdroj: |
American Journal of Physiology: Regulatory, Integrative & Comparative Physiology; 2014, Vol. 307 Issue 1, pR13-R25, 13p |
| Abstrakt: |
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-ɢ (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 HIFdependent RNA levels were assessed. In the brain, HIF-1ɢ was paradoxically decreased at mild anemia, returned to baseline at moderate anemia, and then increased at severe anemia. Brain HIF-2ɢ remained unchanged at all Hb levels. Both kidney HIF-1ɢ and HIF-2ɢ increased earlier (Hb ~70-90 g/l) in response to anemia. Liver also exhibited an early HIF- 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 HIFɢ were nNOS-dependent, our current data demonstrate that increased renal HIFɢ 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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