Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients
Abstract 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 sin...
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Nature Portfolio
2021
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oai:doaj.org-article:bdccddf5b20441ff9d36a503e8db992b2021-12-02T12:09:18ZPreservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients10.1038/s41598-021-83274-12045-2322https://doaj.org/article/bdccddf5b20441ff9d36a503e8db992b2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83274-1https://doaj.org/toc/2045-2322Abstract 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.Thomas DuflotCharlotte LaurentAnne SoudeyXavier FonroseMouad HamzaouiMichèle IacobDominique BertrandJulie FavreIsabelle EtienneClothilde RocheDavid CoquerelMaëlle Le BesneraisSafa LouhichiTracy TarletDongyang LiValéry BrunelChristophe MorisseauVincent RichardRobinson JoannidèsFrançoise Stanke-LabesqueFabien LamoureuxDominique GuerrotJérémy BellienNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
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Medicine R Science Q Thomas Duflot Charlotte Laurent Anne Soudey Xavier Fonrose Mouad Hamzaoui Michèle Iacob Dominique Bertrand Julie Favre Isabelle Etienne Clothilde Roche David Coquerel Maëlle Le Besnerais Safa Louhichi Tracy Tarlet Dongyang Li Valéry Brunel Christophe Morisseau Vincent Richard Robinson Joannidès Françoise Stanke-Labesque Fabien Lamoureux Dominique Guerrot Jérémy Bellien Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients |
| description |
Abstract 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. |
| format |
article |
| author |
Thomas Duflot Charlotte Laurent Anne Soudey Xavier Fonrose Mouad Hamzaoui Michèle Iacob Dominique Bertrand Julie Favre Isabelle Etienne Clothilde Roche David Coquerel Maëlle Le Besnerais Safa Louhichi Tracy Tarlet Dongyang Li Valéry Brunel Christophe Morisseau Vincent Richard Robinson Joannidès Françoise Stanke-Labesque Fabien Lamoureux Dominique Guerrot Jérémy Bellien |
| author_facet |
Thomas Duflot Charlotte Laurent Anne Soudey Xavier Fonrose Mouad Hamzaoui Michèle Iacob Dominique Bertrand Julie Favre Isabelle Etienne Clothilde Roche David Coquerel Maëlle Le Besnerais Safa Louhichi Tracy Tarlet Dongyang Li Valéry Brunel Christophe Morisseau Vincent Richard Robinson Joannidès Françoise Stanke-Labesque Fabien Lamoureux Dominique Guerrot Jérémy Bellien |
| author_sort |
Thomas Duflot |
| title |
Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients |
| title_short |
Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients |
| title_full |
Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients |
| title_fullStr |
Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients |
| title_full_unstemmed |
Preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients |
| title_sort |
preservation of epoxyeicosatrienoic acid bioavailability prevents renal allograft dysfunction and cardiovascular alterations in kidney transplant recipients |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/bdccddf5b20441ff9d36a503e8db992b |
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