Hypoxia inducible factor 1-α is minimally involved in determining the time domains of the hypoxic ventilatory response in adult zebrafish (Danio rerio)

In cell culture, hypoxia stabilizes a transcriptional complex called hypoxia-inducible factor-1 (HIF-1) that increases erythropoietin (Epo) formation. One hallmark of HIF-1 responses is that they can be induced by iron chelation. The first aim of this study was to examine whether an infusion of desferrioxamine (DFO) increased serum Epo in humans. If so, this might provide a paradigm for identifying other HIF-1 responses in humans. Consequently a second aim was to determine whether an infusion of DFO would mimic prolonged hypoxia and increase the acute hypoxic ventilatory response (AHVR). Sixteen volunteers undertook two protocols: 1) continuous infusion of DFO over 8 h and 2) control. Epo and AHVR were measured at fixed times during and after the protocols. The results show that 1) compared with control, Epo increased in most subjects at 8 h [52.8 ± 57.7 vs. 6.9 ± 2.5 (SD) mIU/ml, for DFO = 4 g/70 kg body wt, P < 0.05] and 12 h (63.7 ± 76.3 vs. 7.3 ± 2.5 mIU/ml, P < 0.001) after the start of DFO administration and 2) DFO had no significant effect on AHVR. We conclude that, whereas infusions of DFO mimic hypoxia by increasing Epo, they do not mimic prolonged hypoxia by augmenting AHVR.

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The role of TASK-2 channels in CO2 sensing in zebrafish (Danio rerio)

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00132.2020 ◽

2020 ◽

Vol 319 (3) ◽

pp. R329-R342

Author(s):

N. Koudrina ◽

S. F. Perry ◽

K. M. Gilmour

Keyword(s):

Danio Rerio ◽

Ventilatory Response ◽

Indirect Evidence ◽

Adult Zebrafish ◽

Larval Zebrafish ◽

Neuroepithelial Cells ◽

Cardiorespiratory Reflexes ◽

Or Task ◽

And Task

Peripheral chemosensitivity in fishes is thought to be mediated by serotonin-enriched neuroepithelial cells (NECs) that are localized to the gills of adults and the integument of larvae. In adult zebrafish ( Danio rerio), branchial NECs are presumed to mediate the cardiorespiratory reflexes associated with hypoxia or hypercapnia, whereas in larvae, there is indirect evidence linking cutaneous NECs to hypoxic hyperventilation and hypercapnic tachycardia. No study yet has examined the ventilatory response of larval zebrafish to hypercapnia, and regardless of developmental stage, the signaling pathways involved in CO2 sensing remain unclear. In the mouse, a background potassium channel (TASK-2) contributes to the sensitivity of chemoreceptor cells to CO2. Zebrafish possess two TASK-2 channel paralogs, TASK-2 and TASK-2b, encoded by kcnk5a and kcnk5b, respectively. The present study aimed to determine whether TASK-2 channels are expressed in NECs of larval zebrafish and whether they are involved in CO2 sensing. Using immunohistochemical approaches, TASK-2 protein was observed on the surface of NECs in larvae. Exposure of larvae to hypercapnia caused cardiac and breathing frequencies to increase, and these responses were blunted in fish experiencing TASK-2 and/or TASK-2b knockdown. The results of these experiments suggest that TASK-2 channels are involved in CO2 sensing by NECs and contribute to the initiation of reflex cardiorespiratory responses during exposure of larvae to hypercapnia.

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Hypoxia-inducible factor-1 mediates adaptive developmental plasticity of hypoxia tolerance in zebrafish, Danio rerio

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2014.0637 ◽

2014 ◽

Vol 281 (1786) ◽

pp. 20140637 ◽

Cited By ~ 50

Author(s):

Cayleih E. Robertson ◽

Patricia A. Wright ◽

Louise Köblitz ◽

Nicholas J. Bernier

Keyword(s):

Danio Rerio ◽

Cellular Response ◽

Developmental Plasticity ◽

Developmental Stages ◽

Critical Role ◽

Hypoxia Inducible Factor ◽

Hypoxia Tolerance ◽

Anthropogenic Factors ◽

Critical Window ◽

Hypoxia Inducible Factor 1

In recent years, natural and anthropogenic factors have increased aquatic hypoxia the world over. In most organisms, the cellular response to hypoxia is mediated by the master regulator hypoxia-inducible factor-1 (HIF-1). HIF-1 also plays a critical role in the normal development of the cardiovascular system of vertebrates. We tested the hypothesis that hypoxia exposures which resulted in HIF-1 induction during embryogenesis would be associated with enhanced hypoxia tolerance in subsequent developmental stages. We exposed zebrafish ( Danio rerio ) embryos to just 4 h of severe hypoxia or total anoxia at 18, 24 and 36 h post-fertilization (hpf). Of these, exposure to hypoxia at 24 and 36 hpf as well as anoxia at 36 hpf activated the HIF-1 cellular pathway. Zebrafish embryos that acutely upregulated the HIF-1 pathway had an increased hypoxia tolerance as larvae. The critical window for hypoxia sensitivity and HIF-1 signalling was 24 hpf. Adult male fish had a lower critical oxygen tension ( P crit ) compared with females. Early induction of HIF-1 correlated directly with an increased proportion of males in the population. We conclude that mounting a HIF-1 response during embryogenesis is associated with long-term impacts on the phenotype of later stages which could influence both individual hypoxia tolerance and population dynamics.

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Time domains of the hypoxic ventilatory response

Respiration Physiology ◽

10.1016/s0034-5687(98)00026-7 ◽

1998 ◽

Vol 112 (2) ◽

pp. 123-134 ◽

Cited By ~ 427

Author(s):

F.L Powell ◽

W.K Milsom ◽

G.S Mitchell

Keyword(s):

Ventilatory Response ◽

Hypoxic Ventilatory Response ◽

Time Domains

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Time domains of the hypoxic ventilatory response in awake ducks: episodic and continuous hypoxia

Respiration Physiology ◽

10.1016/s0034-5687(00)00197-3 ◽

2001 ◽

Vol 124 (2) ◽

pp. 117-128 ◽

Cited By ~ 49

Author(s):

G.S Mitchell ◽

F.L Powell ◽

S.R Hopkins ◽

W.K Milsom

Keyword(s):

Ventilatory Response ◽

Hypoxic Ventilatory Response ◽

Time Domains

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TibetanPHD2, an allele with loss-of-function properties

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1920546117 ◽

2020 ◽

Vol 117 (22) ◽

pp. 12230-12238 ◽

Cited By ~ 3

Author(s):

Daisheng Song ◽

Bradleigh E. Navalsky ◽

Wei Guan ◽

Cassandra Ingersoll ◽

Tao Wang ◽

...

Keyword(s):

High Altitude ◽

Chronic Hypoxia ◽

Ventilatory Response ◽

Hypoxia Inducible Factor ◽

Systolic Pressure ◽

Genetic Alterations ◽

Hypoxic Ventilatory Response ◽

Loss Of Function ◽

Ventricular Systolic Pressure

Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway,PHD2andHIF2A. The product of the former induces the degradation of the product of the latter. Key issues regarding TibetanPHD2are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that TibetanPHD2is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the TibetanPhd2allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal. This is phenocopied by mice with a mutation inp23that abrogates the PHD2:p23 interaction.Hif2ahaploinsufficiency, but not the TibetanPhd2allele, ameliorates hypoxia-induced increases in right ventricular systolic pressure. The TibetanPhd2allele is not associated with hemoglobin levels in mice. We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude.

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Time domains of the hypoxic ventilatory response in ectothermic vertebrates

Journal of Comparative Physiology B ◽

10.1007/s00360-011-0554-6 ◽

2011 ◽

Vol 181 (3) ◽

pp. 311-333 ◽

Cited By ~ 21

Author(s):

Cosima Porteus ◽

Michael S. Hedrick ◽

James W. Hicks ◽

Tobias Wang ◽

William K. Milsom

Keyword(s):

Ventilatory Response ◽

Hypoxic Ventilatory Response ◽

Time Domains

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Aquatic surface respiration improves survival during hypoxia in zebrafish ( Danio rerio ) lacking hypoxia-inducible factor 1-α

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2021.1863 ◽

2022 ◽

Vol 289 (1966) ◽

Author(s):

Milica Mandic ◽

Kaitlyn Flear ◽

Pearl Qiu ◽

Yihang K. Pan ◽

Steve F. Perry ◽

...

Keyword(s):

Danio Rerio ◽

Hypoxia Inducible Factor ◽

Hypoxia Tolerance ◽

Wild Type ◽

Survival Times ◽

Aquatic Surface Respiration ◽

Negative Effects ◽

Hypoxia Inducible Factor 1 ◽

Impact On Survival ◽

The Impact

Hypoxia-inducible factor 1-α (Hif-1α), an important transcription factor regulating cellular responses to reductions in O 2 , previously was shown to improve hypoxia tolerance in zebrafish ( Danio rerio ). Here, we examined the contribution of Hif-1α to hypoxic survival, focusing on the benefit of aquatic surface respiration (ASR). Wild-type and Hif-1α knockout lines of adult zebrafish were exposed to two levels (moderate or severe) of intermittent hypoxia. Survival was significantly compromised in Hif-1α knockout zebrafish prevented from accessing the surface during severe (16 mmHg) but not moderate (23 mmHg) hypoxia. When allowed access to the surface in severe hypoxia, survival times did not differ between wild-type and Hif-1α knockouts. Performing ASR mitigated the negative effects of the loss of Hif-1α with the knockouts initiating ASR at a higher P O 2 threshold and performing ASR for longer than wild-types. The loss of Hif-1α had little impact on survival in fish between 1 and 5 days post-fertilization, but as the larvae aged, their reliance on Hif-1α increased. Similar to adult fish, ASR compensated for the loss of Hif-1α on survival. Together, these results demonstrate that age, hypoxia severity and, in particular, the ability to perform ASR significantly modulate the impact of Hif-1α on survival in hypoxic zebrafish.

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