Differential contribution of renal cytochrome P450 enzymes to kidney endothelial dysfunction and vascular oxidative stress in obesity



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Muñoz Picos, Mercedes and López-Oliva Muñoz, María Elvira and Pinilla Pérez, Estéfano and Rodríguez, Claudia and Martínez Saiz, María Pilar and Contreras Jiménez, Cristina and Gómez, Alfonso and Benedito Castellote, Sara and Sáenz Medina, Javier and Rivera de los Arcos, Luis and Prieto Ocejo, Dolores (2021) Differential contribution of renal cytochrome P450 enzymes to kidney endothelial dysfunction and vascular oxidative stress in obesity. Biochemical Pharmacology, 195 . p. 114850. ISSN 0006-2952

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Official URL: https://doi.org/10.1016/j.bcp.2021.114850


Arachidonic acid (AA)-derived cytochrome P450 (CYP) derivatives, epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetranoic acid (20-HETE), play a key role in kidney tubular and vascular functions and blood pressure. Altered metabolism of CYP epoxygenases and CYP hydroxylases has differentially been involved in the pathogenesis of metabolic disease-associated vascular complications, although the mechanisms responsible for the vascular injury are unclear. The present study aimed to assess whether obesity-induced changes in CYP enzymes may contribute to oxidative stress and endothelial dysfunction in kidney preglomerular arteries. Endothelial function and reactive oxygen species (ROS) production were assessed in interlobar arteries of obese Zucker rats (OZR) and their lean counterparts lean Zucker rats (LZR) and the effects of CYP2C and CYP4A inhibitors sulfaphenazole and HET0016, respectively, were examined on the endothelium-dependent relaxations and O2 − and H2O2 levels of preglomerular arteries. Non-nitric oxide (NO) non-prostanoid endothelium-derived hyperpolarization (EDH)-type responses were preserved but resistant to the CYP epoxygenase blocker sulfaphenazole in OZR in contrast to those in LZR. Sulfaphenazole did not further inhibit reduced arterial H2O2 levels, and CYP2C11/CYP2C23 enzymes were downregulated in intrarenal arteries from OZR. Renal EDH-mediated relaxations were preserved in obese rats by the enhanced activity and expression of endothelial calcium-activated potassium channels (KCa). CYP4A blockade restored impaired NO-mediated dilatation and inhibited augmented O2 − production in kidney arteries from OZR. The current data demonstrate that both decreased endothelial CYP2C11/ CYP2C23-derived vasodilator H2O2 and augmented CYP4A-derived 20-HETE contribute to endothelial dysfunction and vascular oxidative stress in obesity. CYP4A inhibitors ameliorate arterial oxidative stress and restore endothelial function which suggests its therapeutic potential for the vascular complications of obesity-associated kidney injury.

Item Type:Article
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CRUE-CSIC (Acuerdos Transformativos 2021)

Uncontrolled Keywords:CYP2C epoxygenases; CYP4 hydroxylase; Endothelial dysfunction; Reactive oxygen species; Kidney preglomerular arteries; Obesity
Subjects:Medical sciences > Medicine > Physiology
Medical sciences > Medicine > Nephrology and Urology
Medical sciences > Pharmacy > Animal physiology
ID Code:70462
Deposited On:15 Feb 2022 10:17
Last Modified:21 Feb 2022 15:14

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