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

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 PI3Kas 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

Google maps for tissues: Multiscale imaging of biological systems and disease

“…13,14 Renal MRI is noninvasive, affords full kidney coverage, excellent soft tissue contrast, high temporal resolution, and longitudinal studies without ionizing radiation, 15,16 as illustrated by Figure 1 showing multi-parametric MRI for probing different physiological parameters at different spatial scales using T 1 , T 2 , T 2 *, blood oxygenation level dependent, apparent water diffusion and renal blood volume contrast. 13,14 Renal MRI is noninvasive, affords full kidney coverage, excellent soft tissue contrast, high temporal resolution, and longitudinal studies without ionizing radiation, 15,16 as illustrated by Figure 1 showing multi-parametric MRI for probing different physiological parameters at different spatial scales using T 1 , T 2 , T 2 *, blood oxygenation level dependent, apparent water diffusion and renal blood volume contrast.…”

“…Functional MRI of the kidney may serve as a striking example: state-of-the-art renal MRI allows investigators to qualitatively assess physiological parameters such as renal blood flow, GFR and oxygenation. 13,14 Renal MRI is noninvasive, affords full kidney coverage, excellent soft tissue contrast, high temporal resolution, and longitudinal studies without ionizing radiation, 15,16 as illustrated by Figure 1 showing multi-parametric MRI for probing different physiological parameters at different spatial scales using T 1 , T 2 , T 2 *, blood oxygenation level dependent, apparent water diffusion and renal blood volume contrast. Yet, the validity of functional MRI techniques for renal parameters for various (patho-)physiological scenarios remains to be established.…”

Protection against acute kidney injury is afforded by a 14,15‐epoxy‐eicosatrienoic acid (EET) analog—A potential druggable pathway

“…2 EETs by contrast are mainly derived from the vascular endothelium, and some may act as vasodilators that attenuate inflammation and hypertension. 1 Notably, at 48-hours follow-up, the EET-treated rats displayed plasma creatinine and urea concentrations and thus creatinine clearance values not different from control rats. 3 The authors exploited previous data showing that (a) modification of the 14,15-EET into a more stable urea bioisostere still yielded potent vascular relaxation, 4 and (b) 14,15-EET is a vasodilator in the perfused kidney.…”

“…Arachidonic acid can be metabolized by 3 distinct pathways: lipoxygenase, cyclooxygenase and CYPs. The investigators of the Acta Physiologica study 1 have shown previously in mice that deletion of the enzyme responsible for degradation and inactivation of EET, soluble epoxide hydrolase (sEH), elevated EET expectedly but did not exert the predicted protective effect on GFR and tissue injury after 22 minutes kidney ischaemia insult and 2-day follow-up. Both fatty acid derivatives are short lived; they are produced by the kidneys, and substantial data show that 20-HETE is a vasoconstrictor in the renal vascular bed involved in autoregulation of blood flow by myogenic and tubuloglomerular feedback mechanisms and as an amplifier of the vasoconstrictor action of endothelin and angiotensin II (reviewed by Fan and Roman).…”

“…CYP enzymes synthesize EET regioisomers: 5,6-EET, 8,9-EET, 11,12-EET and 14,15-EET, and this is of functional relevance since diameter responses to regioisomers differ in kidneys. 1 It was concluded that detrimental upregulation of 20-HETE formation in response to ischaemia-reperfusion could be mitigated by pre-treatment with a more stable EET analog in an animal model of kidney injury. 3 While 20-HETE has been tested in numerous studies for a negative role in ischaemia-reperfusion injury, surprisingly few studies have addressed the potential protective effect of selected EETs in ischaemia-reperfusion injury in kidneys.…”