Inhibition of Endothelial PHD2 Suppresses Post-Ischemic Kidney Inflammation through Hypoxia-Inducible Factor-1.
Acute Kidney Injury
/ genetics
Animals
Basic Helix-Loop-Helix Transcription Factors
/ metabolism
Cell Hypoxia
Disease Models, Animal
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
/ metabolism
Hypoxia-Inducible Factor-Proline Dioxygenases
/ genetics
Mice
Procollagen-Proline Dioxygenase
/ genetics
Reperfusion Injury
/ prevention & control
Sensitivity and Specificity
Signal Transduction
/ genetics
HIF
PHD2
endothelium
ischemia-reperfusion
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
21
05
2019
accepted:
15
11
2019
pubmed:
31
1
2020
medline:
11
11
2020
entrez:
31
1
2020
Statut:
ppublish
Résumé
Prolyl-4-hydroxylase domain-containing proteins 1-3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined. To investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2. Endothelial deletion of Our findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.
Sections du résumé
BACKGROUND
Prolyl-4-hydroxylase domain-containing proteins 1-3 (PHD1 to PHD3) regulate the activity of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2, transcription factors that are key regulators of hypoxic vascular responses. We previously reported that deficiency of endothelial HIF-2 exacerbated renal ischemia-reperfusion injury, whereas inactivation of endothelial PHD2, the main oxygen sensor, provided renoprotection. Nevertheless, the molecular mechanisms by which endothelial PHD2 dictates AKI outcomes remain undefined.
METHODS
To investigate the function of the endothelial PHD2/HIF axis in ischemic AKI, we examined the effects of endothelial-specific ablation of PHD2 in a mouse model of renal ischemia-reperfusion injury. We also interrogated the contribution of each HIF isoform by concurrent endothelial deletion of both PHD2 and HIF-1 or both PHD2 and HIF-2.
RESULTS
Endothelial deletion of
CONCLUSIONS
Our findings suggest that activation of endothelial HIF-1 signaling through PHD2 inhibition may offer a novel therapeutic approach against ischemic AKI.
Identifiants
pubmed: 31996410
pii: ASN.2019050523
doi: 10.1681/ASN.2019050523
pmc: PMC7062211
doi:
Substances chimiques
Basic Helix-Loop-Helix Transcription Factors
0
Hypoxia-Inducible Factor 1, alpha Subunit
0
PHD3 protein, mouse
EC 1.14.11.2
Procollagen-Proline Dioxygenase
EC 1.14.11.2
Egln1 protein, mouse
EC 1.14.11.29
Hypoxia-Inducible Factor-Proline Dioxygenases
EC 1.14.11.29
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
501-516Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK115850
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103326
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM104936
Pays : United States
Informations de copyright
Copyright © 2020 by the American Society of Nephrology.
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