Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Departamento de Anatomía y Embriología, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain.
Biochem Pharmacol. 2022 Jan;195:114850. doi: 10.1016/j.bcp.2021.114850. Epub 2021 Nov 22.
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 O and HO 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 HO 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 (K). CYP4A blockade restored impaired NO-mediated dilatation and inhibited augmented O production in kidney arteries from OZR. The current data demonstrate that both decreased endothelial CYP2C11/ CYP2C23-derived vasodilator HO 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.
花生四烯酸（AA）衍生的细胞色素 P450（CYP）衍生物，环氧二十碳三烯酸（EETs）和 20-羟二十碳四烯酸（20-HETE），在肾脏管状和血管功能以及血压中发挥关键作用。CYP 加氧酶和 CYP 羟化酶代谢的改变已经不同程度地参与了代谢性疾病相关血管并发症的发病机制，尽管导致血管损伤的机制尚不清楚。本研究旨在评估肥胖引起的 CYP 酶变化是否可能导致肾小球前动脉的氧化应激和内皮功能障碍。在肥胖型 Zucker 大鼠（OZR）和其 lean 型 Zucker 大鼠（LZR）的叶间动脉中评估内皮功能和活性氧（ROS）的产生，并分别用 CYP2C 和 CYP4A 抑制剂磺胺酚唑和 HET0016 研究它们对肾小球前动脉的内皮依赖性舒张作用和 O 和 HO 水平的影响。非一氧化氮（NO）非前列环素内皮衍生超极化（EDH）型反应在 OZR 中被保留，但对 CYP 加氧酶阻断剂磺胺酚唑有抗性，而在 LZR 中则没有。磺胺酚唑并没有进一步抑制动脉 HO 水平的降低，并且 CYP2C11/CYP2C23 酶在 OZR 的肾内动脉中下调。肥胖大鼠的肾脏 EDH 介导的松弛通过内皮钙激活钾通道（K）的活性和表达增强而得到保留。CYP4A 阻断恢复了 OZR 肾脏血管中受损的 NO 介导的扩张，并抑制了增强的 O 产生。目前的数据表明，内皮 CYP2C11/CYP2C23 衍生的血管舒张剂 HO 的减少和 CYP4A 衍生的 20-HETE 的增加都导致了肥胖中的内皮功能障碍和血管氧化应激。CYP4A 抑制剂改善了动脉氧化应激并恢复了内皮功能，这表明其对肥胖相关肾损伤的血管并发症具有治疗潜力。
