Uwe Hoff1, Gordana Bubalo1, Mandy Fechner1, Maximilian Blum2, Ye Zhu1,3, Andreas Pohlmann4, Jan Hentschel4, Karen Arakelyan4,5, Erdmann Seeliger5, Bert Flemming5, Dennis Gürgen1, Michael Rothe6, Thoralf Niendorf2,4, Vijaya L Manthati7, John R Falck7, Michael Haase8,9, Wolf-Hagen Schunck2, Duska Dragun1. 1. Nephrology and Intensive Care Medicine, Center for Cardiovascular Research, Charité-Universitätsmedizin Berlin, Berlin, Germany. 2. Max Delbrueck Center for Molecular Medicine, Berlin, Germany. 3. Department of Nephrology, The Fifth Affiliated Hospital of Sun Yat-sun University, Zhuhai, China. 4. Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrueck Center for Molecular Medicine, Berlin, Germany. 5. Center for Cardiovascular Research, Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany. 6. Lipidomix GmbH, Berlin, Germany. 7. Biochemistry Department, UT Southwestern, Dallas, Texas. 8. Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany. 9. Diaverum Deutschland, Potsdam, Germany.
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.
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.
Authors: K Nithipatikom; R F DiCamelli; S Kohler; R J Gumina; J R Falck; W B Campbell; G J Gross Journal: Anal Biochem Date: 2001-05-01 Impact factor: 3.365
Authors: Agnieszka Walkowska; Luděk Červenka; John D Imig; John R Falck; Janusz Sadowski; Elżbieta Kompanowska-Jezierska Journal: Front Physiol Date: 2021-01-28 Impact factor: 4.566