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PHD1-3 oxygen sensors in vivo—lessons learned from gene deletions


Jucht, Agnieszka E; Scholz, Carsten C (2024). PHD1-3 oxygen sensors in vivo—lessons learned from gene deletions. Pflügers Archiv : European Journal of Physiology:Epub ahead of print.

Abstract

Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), afecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1–3 (PHD1-3; also called Egln1-3, HIF-P4H 1–3, HIF-PH 1–3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be benefcial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not benefcial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.

Abstract

Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), afecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1–3 (PHD1-3; also called Egln1-3, HIF-P4H 1–3, HIF-PH 1–3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be benefcial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not benefcial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Physiology
Life Sciences > Clinical Biochemistry
Health Sciences > Physiology (medical)
Language:English
Date:21 March 2024
Deposited On:25 Apr 2024 06:35
Last Modified:30 Jun 2024 01:41
Publisher:Springer
ISSN:0031-6768
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1007/s00424-024-02944-x
PubMed ID:38509356
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)