| First Author | Tsui AK | Year | 2014 |
| Journal | Am J Physiol Regul Integr Comp Physiol | Volume | 307 |
| Issue | 1 | Pages | R13-25 |
| PubMed ID | 24760996 | Mgi Jnum | J:240918 |
| Mgi Id | MGI:5896723 | Doi | 10.1152/ajpregu.00411.2013 |
| Citation | Tsui AK, et al. (2014) Differential HIF and NOS responses to acute anemia: defining organ-specific hemoglobin thresholds for tissue hypoxia. Am J Physiol Regul Integr Comp Physiol 307(1):R13-25 |
| abstractText | 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-alpha (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-1alpha was paradoxically decreased at mild anemia, returned to baseline at moderate anemia, and then increased at severe anemia. Brain HIF-2alpha remained unchanged at all Hb levels. Both kidney HIF-1alpha and HIF-2alpha increased earlier (Hb approximately 70-90 g/l) in response to anemia. Liver also exhibited an early HIF-alpha response. Carotid blood flow was increased early (Hb approximately 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 HIFalpha were nNOS-dependent, our current data demonstrate that increased renal HIFalpha was nNOS independent. HIF-dependent RNA levels increased linearly ( approximately 10-fold) in the brain. However, renal HIF-RNA responses (MCT4, EPO) increased exponentially ( approximately 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. |
