A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury.
8,11,14-Eicosatrienoic Acid
/ administration & dosage
Acute Kidney Injury
/ pathology
Animals
Cardiac Surgical Procedures
/ adverse effects
Fatty Acids
/ chemistry
Humans
Hydroxyeicosatetraenoic Acids
/ blood
Ischemia
/ etiology
Kidney
/ metabolism
Male
Postoperative Complications
Rats
Rats, Inbred Lew
Reperfusion Injury
/ metabolism
Signal Transduction
CYP-eicosanoids
acute kidney injury
inflammation
reoxygenation
signalling
Journal
Acta physiologica (Oxford, England)
ISSN: 1748-1716
Titre abrégé: Acta Physiol (Oxf)
Pays: England
ID NLM: 101262545
Informations de publication
Date de publication:
10 2019
10 2019
Historique:
received:
15
10
2018
revised:
08
05
2019
accepted:
08
05
2019
pubmed:
12
5
2019
medline:
1
9
2020
entrez:
12
5
2019
Statut:
ppublish
Résumé
Imbalances in cytochrome P450 (CYP)-dependent eicosanoid formation may play a central role in ischemic acute kidney injury (AKI). We reported previously that inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) action ameliorated ischemia/reperfusion (I/R)-induced AKI in rats. Now we tested the hypothesis that enhancement of epoxyeicosatrienoic acid (EET) actions may counteract the detrimental effects of 20-HETE and prevent the initiation of AKI. Male Lewis rats underwent right nephrectomy and ischemia was induced by 45 min clamping of the left renal pedicle followed by up to 48 h of reperfusion. Circulating CYP-eicosanoid profiles were compared in patients who underwent cardiac surgery with (n = 21) and without (n = 38) developing postoperative AKI. Ischemia induced an about eightfold increase of renal 20-HETE levels, whereas free EETs were not accumulated. To compensate for this imbalance, a synthetic 14,15-EET analogue was administered by intrarenal infusion before ischemia. The EET analogue improved renal reoxygenation as monitored by in vivo parametric MRI during the initial 2 h reperfusion phase. The EET analogue improved PI3K- as well as mTORC2-dependent rephosphorylation of Akt, induced inactivation of GSK-3β, reduced the development of tubular apoptosis and attenuated inflammatory cell infiltration. The EET analogue also significantly alleviated the I/R-induced drop in creatinine clearance. Patients developing postoperative AKI featured increased preoperative 20-HETE and 8,9-EET levels. Pharmacological interventions targeting the CYP-eicosanoid pathway could offer promising new options for AKI prevention. Individual differences in CYP-eicosanoid formation may contribute to the risk of developing AKI in clinical settings.
Identifiants
pubmed: 31077555
doi: 10.1111/apha.13297
pmc: PMC6733619
mid: NIHMS1029130
doi:
Substances chimiques
Fatty Acids
0
Hydroxyeicosatetraenoic Acids
0
20-hydroxy-5,8,11,14-eicosatetraenoic acid
79551-86-3
14,15-epoxy-5,8,11-eicosatrienoic acid
81276-03-1
8,11,14-Eicosatrienoic Acid
FC398RK06S
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
e13297Subventions
Organisme : Robert A. Welch Foundation
Pays : International
Organisme : NIGMS NIH HHS
ID : R01 GM031278
Pays : United States
Organisme : National Natural Science Foundation of China
ID : 81600529
Pays : International
Organisme : National Natural Science Foundation of China
ID : 17ykpy64
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : FOR 1368
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.
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