A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury

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Item Type:	Article
Title:	A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury
Creators Name:	Hoff, U., Bubalo, G., Fechner, M., Blum, M., Zhu, Y., Pohlmann, A., Hentschel, J., Arakelyan, K., Seeliger, E., Flemming, B., Gürgen, D., Rothe, M., Niendorf, T., Manthati, V.L., Falck, J.R., Haase, M., Schunck, W.H. and Dragun, D.
Abstract:	AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Keywords:	Acute Kidney Injury, CYP-Eicosanoids, Inflammation, Reoxygenation, Signalling, Animals, Rats
Source:	Acta Physiologica
ISSN:	1748-1708
Publisher:	Wiley
Volume:	227
Number:	2
Page Range:	e13297
Date:	October 2019
Official Publication:	https://doi.org/10.1111/apha.13297
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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