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

Item Type:Article
Title:A synthetic epoxyeicosatrienoic acid analog prevents the initiation of ischemic acute kidney injury
Creators Name:Hoff, U. and Bubalo, G. and Fechner, M. and Blum, M. and Zhu, Y. and Pohlmann, A. and Hentschel, J. and Arakelyan, K. and Seeliger, E. and Flemming, B. and Gürgen, D. and Rothe, M. and Niendorf, T. and Manthati, V.L. and Falck, J.R. and Haase, M. and 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 where compared in patients who underwent cardiac surgery with (n=21) and without (n=38) developing postoperative AKI. RESULTS: Ischemia induced an about 8-fold increase of renal 20-HETE levels, whereas free EETs were not accumulated. To compensate for this imbalance, a synthetic 14,15-EET analog was administered by intrarenal infusion before ischemia. The EET analog improved renal reoxygenation as monitored by in vivo parametric MRI during the initial 2 h reperfusion phase. The EET analog 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 analog 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 (U.K.)
Page Range:e13297
Date:11 May 2019
Official Publication:https://doi.org/10.1111/apha.13297
PubMed:View item in PubMed

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