Vasopressin lowers renal epoxyeicosatrienoic acid levels by activating soluble epoxide hydrolase

Boldt, Christin; Röschel, Tom; Himmerkus, Nina; Plain, Allein; Labes, Robert; Blum, M; Krause, Hans; Magheli, Ahmed; Giesecke, Torsten; Mutig, Kerim; Rothe, Michael; Weldon, Steven M.; Dragun, Duska; Schunck, Wolf‐Hagen; Bachmann, S.; Paliege, Alexander

doi:10.1152/ajprenal.00062.2016

Cited by 3 publications

(2 citation statements)

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“…The study has shown that HDP patients secrete large amounts of 14,15-EET in their urine, suggesting that 14,15-EET might have a regulatory effect on HDP [24]. EETs are also produced in the placenta, trophoblast cells, amniotic membrane, chorion, decidua, and myometrium of the pregnant uterus, and increased EETs levels in the embryo-placenta are more significant than those in plasma [25]. EETs contribute to the physiological response to normal pregnancy and the pathophysiology of pregnancy-induced hypertension [26].…”

Section: Discussionmentioning

confidence: 98%

Levels and Significance of Arachidonic Acid Metabolites in Hypertensive Disorders of Pregnancy: A Prospective Cohort Study

Cao,

Yang,

Zhu

et al. 2023

Clin. Exp. Obstet. Gynecol.

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Background: This project aimed to investigate the role of two arachidonic acid metabolites (14, and 15-hydroxyeicosateraenoic acid (15-HETE)) as a precursor of hypertensive disorders in pregnancy by comparing their serum levels between third-trimester hypertensive and normal pregnant women. The relationship between their differential levels and pregnancy outcomes was investigated to clarify the role of arachidonic acid metabolites in the occurrence and development of hypertensive disorders during pregnancy. Methods: This is a prospective cohort study and a total of 88 patients were included in the study. 17 of them were recognized as the gestational hypertension and 25 of them were considered to be the preeclampsia. 24 women were diagnosed with severe preeclampsia. The control group consisted of 22 healthy patients pregnancy course, with no disease at the present and in the history. For this purpose, the serum levels of 14,15-EET and 15-HETE of gestational hypertension, preeclampsia (PE) and normal pregnant women group were detected by enzyme-linked immunosorbent assay (ELISA) during the third trimester of pregnancy. It was followed by detecting placental cytochrome P450 2J2 (CYP2J2) and 15-lipoxygenase-2 (15-LOX-2) expression and localization using immunohistochemistry, their corresponding proteins employing western blotting. All outcomes of maternal pregnancy were then statistically analyzed. Results: The analysis indicated that the levels of 14,15-EET, and 15-HETE were significantly higher (p < 0.05) in gestational hypertension compared to control, where the same differences were observed when severe preeclampsia and preeclampsia groups were compared, which were altogether higher than gestational hypertension group patients. Similarly, the 14,15-EET and 15-HETE levels were significantly (p < 0.05) higher in the adverse pregnancy outcome than in the normal pregnancy outcome group in severe preeclampsia. The immunohistochemical analysis results revealed that the positive staining for CYP2J2 and 15-LOX-2 expression in the placenta of the preeclampsia group was significant (p < 0.05) compared to the normal pregnant control and gestational hypertension groups, with significantly higher (p < 0.05) relative CYP2J2 and 15-LOX-2 protein levels in preeclampsia compared to normal control pregnancy group. Conclusions: The study concluded that the 14,15-EET and 15-HETE might be involved in gestational hypertension pathophysiology and preeclampsia, associated with disease severity and adverse pregnancy outcomes. Moreover, CYP2J2 and 15-LOX-2 signaling expression in the placenta may be related to arachidonic acid metabolites generated in preeclampsia.

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Section: Discussionmentioning

confidence: 98%

Levels and Significance of Arachidonic Acid Metabolites in Hypertensive Disorders of Pregnancy: A Prospective Cohort Study

Cao,

Yang,

Zhu

et al. 2023

Clin. Exp. Obstet. Gynecol.

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“…Free tissue levels of eicosanoids and related lipid mediators were determined by mass spectrometry as previously described ( Boldt et al, 2016 ). In brief, kidney samples were finely ground in liquid nitrogen and dissolved in a 50/50 vol/vol mixture of water and methanol supplemented with 0.01% butylhydroxytoluol.…”

Section: Methodsmentioning

confidence: 99%

Annexin A1 exerts renoprotective effects in experimental crescentic glomerulonephritis

et al. 2022

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Non-resolving inflammation plays a critical role during the transition from renal injury towards end-stage renal disease. The glucocorticoid-inducible protein annexin A1 has been shown to function as key regulator in the resolution phase of inflammation, but its role in immune-mediated crescentic glomerulonephritis has not been studied so far.Methods: Acute crescentic glomerulonephritis was induced in annexin A1-deficient and wildtype mice using a sheep serum against rat glomerular basement membrane constituents. Animals were sacrificed at d5 and d10 after nephritis induction. Renal leukocyte abundance was studied by immunofluorescence and flow cytometry. Alterations in gene expression were determined by RNA-Seq and gene ontology analysis. Renal levels of eicosanoids and related lipid products were measured using lipid mass spectrometry.Results: Histological analysis revealed an increased number of sclerotic glomeruli and aggravated tubulointerstitial damage in the kidneys of annexin A1-deficient mice compared to the wildtype controls. Flow cytometry analysis confirmed an increased number of CD45+ leukocytes and neutrophil granulocytes in the absence of annexin A1. Lipid mass spectrometry showed elevated levels of prostaglandins PGE2 and PGD2 and reduced levels of antiinflammatory epoxydocosapentaenoic acid regioisomers. RNA-Seq with subsequent gene ontology analysis revealed induction of gene products related to leukocyte activation and chemotaxis as well as regulation of cytokine production and secretion.Conclusion: Intrinsic annexin A1 reduces proinflammatory signals and infiltration of neutrophil granulocytes and thereby protects the kidney during crescentic glomerulonephritis. The annexin A1 signaling cascade may therefore provide novel targets for the treatment of inflammatory kidney disease.

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Cytochrome P450 epoxygenase‐derived 5,6‐epoxyeicosatrienoic acid relaxes pulmonary arteries in normoxia but promotes sustained pulmonary vasoconstriction in hypoxia

et al. 2020

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AimsThe aim of the study was to investigate the role of cytochrome P450 (CYP) epoxygenase‐derived epoxyeicosatrienoic acids (EETs) in sustained hypoxic pulmonary vasoconstriction (HPV).MethodsVasomotor responses of isolated mouse intrapulmonary arteries (IPAs) were assessed using wire myography. Key findings were verified by haemodynamic measurements in isolated perfused and ventilated mouse lungs.ResultsPharmacological inhibition of EET synthesis with MS‐PPOH, application of the EET antagonist 14,15‐EEZE or deficiency of CYP2J isoforms suppressed sustained HPV. In contrast, knockdown of EET‐degrading soluble epoxide hydrolase or its inhibition with TPPU augmented sustained HPV almost twofold. All EET regioisomers elicited relaxation in IPAs pre‐contracted with thromboxane mimetic U46619. However, in the presence of KCl‐induced depolarization, 5,6‐EET caused biphasic contraction in IPAs and elevation of pulmonary vascular tone in isolated lungs, whereas other regioisomers had no effect. In patch‐clamp experiments, hypoxia elicited depolarization in pulmonary artery smooth muscle cells (PASMCs), and 5,6‐EET evoked inward whole cell currents in PASMCs depolarized to the hypoxic level, but not at their resting membrane potential.ConclusionsThe EET pathway substantially contributes to sustained HPV in mouse pulmonary arteries. 5,6‐EET specifically appears to be involved in HPV, as it is the only EET regioisomer able to elicit not only relaxation, but also sustained contraction in these vessels. 5,6‐EET‐induced pulmonary vasoconstriction is enabled by PASMC depolarization, which occurs in hypoxia. The discovery of the dual role of 5,6‐EET in the regulation of pulmonary vascular tone may provide a basis for the development of novel therapeutic strategies for treatment of HPV‐related diseases.

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Vasopressin lowers renal epoxyeicosatrienoic acid levels by activating soluble epoxide hydrolase

Cited by 3 publications

References 74 publications

Levels and Significance of Arachidonic Acid Metabolites in Hypertensive Disorders of Pregnancy: A Prospective Cohort Study

Levels and Significance of Arachidonic Acid Metabolites in Hypertensive Disorders of Pregnancy: A Prospective Cohort Study

Annexin A1 exerts renoprotective effects in experimental crescentic glomerulonephritis

Cytochrome P450 epoxygenase‐derived 5,6‐epoxyeicosatrienoic acid relaxes pulmonary arteries in normoxia but promotes sustained pulmonary vasoconstriction in hypoxia

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