Differential contribution of renal cytochrome P450 enzymes to kidney endothelial dysfunction and vascular oxidative stress in obesity
| Autor: | Elvira López-Oliva, Dolores Prieto, Estéfano Pinilla, Alfonso Gómez, Javier Sáenz-Medina, Sara Benedito, María Pilar Martínez, Mercedes Muñoz, Luis Rivera, Cristina Contreras, Claudia Rodríguez |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Epoxygenase
Male medicine.medical_specialty Nefrología y urología Amidines Vasodilation Fisiología medicine.disease_cause Sulfaphenazole Kidney Biochemistry Cytochrome P-450 CYP2J2 Renal Artery Cytochrome P-450 Enzyme System Internal medicine Hydroxyeicosatetraenoic Acids medicine Animals Obesity Endothelial dysfunction Cytochrome P450 Family 2 Fisiología animal Pharmacology biology business.industry Cytochrome P450 Hydrogen Peroxide medicine.disease Interlobar arteries Rats Zucker Oxidative Stress medicine.anatomical_structure Endocrinology Steroid 16-alpha-Hydroxylase biology.protein Aryl Hydrocarbon Hydroxylases Endothelium Vascular Cytochrome P-450 CYP4A business Reactive Oxygen Species Oxidative stress medicine.drug |
| Zdroj: | Muñoz Picos, M, López-Oliva, E, Pinilla, E, Rodríguez, C, Pilar Martínez, M, Contreras, C, Gómez, A, Benedito, S, Sáenz-Medina, J, Rivera, L & Prieto, D 2021, ' Differential Contribution of Renal Cytochrome P450 Enzymes to Kidney Endothelial Dysfunction and Vascular Oxidative Stress in Obesity ', Biochemical Pharmacology, pp. 114850 . https://doi.org/10.1016/j.bcp.2021.114850 E-Prints Complutense. Archivo Institucional de la UCM instname |
| ISSN: | 1873-2968 |
| DOI: | 10.1016/j.bcp.2021.114850 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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