Polymorphisms in genes involved in vasoactive eicosanoid synthesis affect cardiovascular risk in renal transplant recipients

Gervasini, Guillermo; Luna, Enrique; García-Pino, Guadalupe; Azevedo, Lilia; Mota-Zamorano, Sonia; Cubero, Juan José

doi:10.1080/03007995.2017.1391757

Cited by 5 publications

(7 citation statements)

References 47 publications

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“…Given the major role of EETs in sustained flow-mediated dilatation [21][22][23] , the reduced EET production in response to the increase in blood flow may promote endothelial dysfunction of conduit arteries in kidney transplant recipients. This mechanism may contribute to the deleterious impact of LoF CYP450 SNPs on cardiovascular outcomes in this population 41 . Furthermore, patients carrying R287Q had a higher magnitude of flow-mediated dilatation but also of endothelium-independent dilatation to GTN.…”

Section: Discussionmentioning

confidence: 95%

Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients

Duflot

Laurent

Soudey

et al. 2021

Sci Rep

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This study addressed the hypothesis that epoxyeicosatrienoic acids (EETs) synthesized by CYP450 and catabolized by soluble epoxide hydrolase (sEH) are involved in the maintenance of renal allograft function, either directly or through modulation of cardiovascular function. The impact of single nucleotide polymorphisms (SNPs) in the sEH gene EPHX2 and CYP450 on renal and vascular function, plasma levels of EETs and peripheral blood monuclear cell sEH activity was assessed in 79 kidney transplant recipients explored at least one year after transplantation. Additional experiments in a mouse model mimicking the ischemia–reperfusion (I/R) injury suffered by the transplanted kidney evaluated the cardiovascular and renal effects of the sEH inhibitor t-AUCB administered in drinking water (10 mg/l) during 28 days after surgery. There was a long-term protective effect of the sEH SNP rs6558004, which increased EET plasma levels, on renal allograft function and a deleterious effect of K55R, which increased sEH activity. Surprisingly, the loss-of-function CYP2C9*3 was associated with a better renal function without affecting EET levels. R287Q SNP, which decreased sEH activity, was protective against vascular dysfunction while CYP2C8*3 and 2C9*2 loss-of-function SNP, altered endothelial function by reducing flow-induced EET release. In I/R mice, sEH inhibition reduced kidney lesions, prevented cardiac fibrosis and dysfunction as well as preserved endothelial function. The preservation of EET bioavailability may prevent allograft dysfunction and improve cardiovascular disease in kidney transplant recipients. Inhibition of sEH appears thus as a novel therapeutic option but its impact on other epoxyfatty acids should be carefully evaluated.

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Section: Discussionmentioning

confidence: 95%

Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients

Duflot

Laurent

Soudey

et al. 2021

Sci Rep

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“…There is a growing body of evidence pointing to AA-derived vasoactive eicosanoids as important players in the cardiorenal function (Gervasini et al, 2015[ 13 ][ 14 ], 2018[ 15 ]; Fang et al, 2018[ 10 ]; Imig, 2019[ 22 ]). These findings, together with the existence of preclinical data linking these AA metabolites to the renal damage induced by hyperglycemia (Luo et al, 2009[ 25 ]; Eid et al, 2013[ 9 ]), suggest that the levels of these eicosanoids could be useful indicators of the presence of DKD in renal patients, a hypothesis we test in the present work.…”

Section: Discussionmentioning

confidence: 99%

Plasma and urinary concentrations of arachidonic acid-derived eicosanoids are associated with diabetic kidney disease

Mota-Zamorano

Robles

López‐Gómez

et al. 2021

EXCLI Journal; 20:Doc698; ISSN 1611-2156

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“…Genotyping was carried out by real-time PCR using commercial TaqMan ® SNP genotype assays from Thermofisher Scientific (Rockford, Il, USA). These SNPs were selected based on previous reports stating their influence on clinical outcomes [18,[22][23][24][25][26].…”

Section: Genetic Analysismentioning

confidence: 99%

“…In this regard, we have previously shown that the onset of post-transplant diabetes mellitus in renal transplant recipients is dependent on the presence of variants in genes expressed in the kidney that participate in the epoxygenase pathway [15]. In addition, these polymorphisms have also been related to the development of renal injury [16,17], and cardiovascular (CV) disease [18], whose risk is greatly elevated in DKD patients. However, in spite of this background, the influence of genetic polymorphisms in the AA epoxygenase route on DKD remains untested.…”

Section: Introductionmentioning

confidence: 99%

Genetics Variants in the Epoxygenase Pathway of Arachidonic Metabolism Are Associated with Eicosanoids Levels and the Risk of Diabetic Nephropathy

Mota-Zamorano

Robles

González

et al. 2021

JCM

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Genes in the epoxygenase pathway of arachidonic acid metabolism leading to vasoactive eicosanoids, mainly 20-hydroxyeicosatetraenoic (20-HETE) and epoxyeicosatrienoic (EETs) acids, have been related to glucose-induced renal damage in preclinical reports. We genotyped 1088 diabetic kidney disease (DKD) patients and controls for seven polymorphisms in five genes (CYP2C8, CYP2J2, CYP4F2, CYP4A11, and EPHX2) along this metabolic route and evaluated their effect on DKD risk, clinical outcomes, and the plasma/urine levels of eicosanoids measured by LC/MS/MS and immunoenzymatic assays. The CYP4F2 433M variant allele was associated with lower incidence of DKD (OR = 0.65 (0.48–0.90), p = 0.008), whilst the CYP2C8*3/*3 genotype was related to increased risk (OR = 3.21 (1.05–9.87), p = 0.036). Patients carrying the 433M allele also showed lower eGFR [median and interquartile range vs. wildtype carriers: 30.8 (19.8) and 33.0 (23.2) mL/min/1.73 m2, p = 0.037). Finally, the 433VM/MM variant genotypes were associated with lower urinary levels of 20-HETE compared with 433VV (3.14 (0.86) vs. 8.45 (3.69) ng/mg Creatinine, p = 0.024). Our results indicate that the CYP4F2 V433M polymorphism, by decreasing 20-HETE levels, may play an important role in DKD.

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Polymorphisms in genes involved in vasoactive eicosanoid synthesis affect cardiovascular risk in renal transplant recipients

Abstract: Our results show, for the first time to our knowledge, that two SNPs in CYP2C8 and CYP2J2, which synthesize EETs, may modify CV outcomes in renal transplant recipients, a population that is already at a high risk of suffering these events.

Cited by 5 publications

References 47 publications

Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients

Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients

Plasma and urinary concentrations of arachidonic acid-derived eicosanoids are associated with diabetic kidney disease

Genetics Variants in the Epoxygenase Pathway of Arachidonic Metabolism Are Associated with Eicosanoids Levels and the Risk of Diabetic Nephropathy

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