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Article: Differential HIF and NOS responses to acute anemia: Defining organ-specific hemoglobin thresholds for tissue hypoxia

TitleDifferential HIF and NOS responses to acute anemia: Defining organ-specific hemoglobin thresholds for tissue hypoxia
Authors
KeywordsHypoxia inducible factor
Hemoglobin threshold
Anemia
Nitric oxide synthase
Issue Date2014
Citation
American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 2014, v. 307, n. 1, p. R13-R25 How to Cite?
AbstractTissue 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. © 2014 the American Physiological Society.
Persistent Identifierhttp://hdl.handle.net/10722/205813
ISSN
2015 Impact Factor: 3.168
2015 SCImago Journal Rankings: 1.663
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorTsui, Albert K Y-
dc.contributor.authorMarsden, Philip Anthony-
dc.contributor.authorDavid Mazer, C.-
dc.contributor.authorSled, John G.-
dc.contributor.authorLee, Keith M.-
dc.contributor.authorHenkelman, R. Mark-
dc.contributor.authorCahill, Lindsay S.-
dc.contributor.authorZhou, Yuqing-
dc.contributor.authorChan, Neville-
dc.contributor.authorLiu, Elaine-
dc.contributor.authorHaré, Gregory M T-
dc.date.accessioned2014-10-06T08:02:24Z-
dc.date.available2014-10-06T08:02:24Z-
dc.date.issued2014-
dc.identifier.citationAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology, 2014, v. 307, n. 1, p. R13-R25-
dc.identifier.issn0363-6119-
dc.identifier.urihttp://hdl.handle.net/10722/205813-
dc.description.abstractTissue 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. © 2014 the American Physiological Society.-
dc.languageeng-
dc.relation.ispartofAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology-
dc.subjectHypoxia inducible factor-
dc.subjectHemoglobin threshold-
dc.subjectAnemia-
dc.subjectNitric oxide synthase-
dc.titleDifferential HIF and NOS responses to acute anemia: Defining organ-specific hemoglobin thresholds for tissue hypoxia-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1152/ajpregu.00411.2013-
dc.identifier.pmid24760996-
dc.identifier.scopuseid_2-s2.0-84903649734-
dc.identifier.volume307-
dc.identifier.issue1-
dc.identifier.spageR13-
dc.identifier.epageR25-
dc.identifier.eissn1522-1490-
dc.identifier.isiWOS:000338921900003-

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