Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Departamento de Anatomía y Embriología, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain.
Redox Biol. 2020 Jan;28:101330. doi: 10.1016/j.redox.2019.101330. Epub 2019 Sep 20.
Oxidative stress-associated endothelial dysfunction is a key pathogenic factor underlying the microvascular complications of metabolic disease. NADPH oxidase (Nox) is a major source of oxidative stress in diabetic nephropathy and chronic kidney disease, despite Nox4 and Nox2 have been identified as relevant sources of vasodilator endothelial HO.The present study was sought to investigate the role of Nox enzymes in renal vascular oxidative stress and endothelial dysfunction in a rat model of genetic obesity. Endothelial function was assessed in intrarenal arteries of obese Zucker rats (OZR) and their counterparts lean Zucker rats (LZR) mounted in microvascular myographs, and superoxide (O) and HO production were measured. Impaired endothelium-dependent relaxations to acetylcholine (ACh) were associated to augmented O generation, but neither ROS scavengers nor the Nox inhibitor apocynin significantly improved these relaxant responses in renal arteries of OZR. Whereas NO contribution to endothelial relaxations was blunted, catalase-sensitive non-NO non-prostanoid relaxations were enhanced in obese rats. Interestingly, NADPH-dependent O production was augmented while NADPH-dependent HO generation was reduced, and cytosolic and mitochondrial SOD were up-regulated in kidney of obese rats. Nox4 was down-regulated in renal arteries and Nox4-dependent HO generation and endothelial relaxation were reduced in OZR. Up-regulation of both Nox2 and Nox1 was associated with augmented O production but reduced HO generation and blunted endothelial Nox2-derived HO-mediated in obese rats. Moreover, increased Nox1-derived O contributed to renal endothelial dysfunction in OZR. In summary, the current data support a main role for Nox1-derived O in kidney vascular oxidative stress and renal endothelial dysfunction in obesity, while reduced endothelial Nox4 expression associated to decreased HO generation and HO-mediated vasodilatation might hinder Nox4 protective renal effects thus contributing to kidney injury. This suggests that effective therapies to counteract oxidative stress and prevent microvascular complications must identify the specific Nox subunits involved in metabolic disease.
氧化应激相关的内皮功能障碍是代谢性疾病微血管并发症的关键致病因素。尽管已经确定 Nox4 和 Nox2 是血管舒张内皮 HO 的相关来源，但 NADPH 氧化酶 (Nox) 是糖尿病肾病和慢性肾脏病中氧化应激的主要来源。本研究旨在探讨 Nox 酶在遗传性肥胖大鼠模型肾血管氧化应激和内皮功能障碍中的作用。在微血管肌动描记器中评估肥胖 Zucker 大鼠 (OZR) 和其 lean Zucker 大鼠 (LZR) 的肾内动脉内皮功能，并测量超氧阴离子 (O) 和 HO 的产生。乙酰胆碱 (ACh) 诱导的内皮依赖性舒张受损与 O 生成增加有关，但 ROS 清除剂或 Nox 抑制剂 apocynin 均不能显著改善 OZR 肾动脉的舒张反应。虽然对内皮舒张作用的 NO 贡献减弱，但肥胖大鼠的过氧化氢酶敏感的非 NO 非前列腺素舒张反应增强。有趣的是，NADPH 依赖性 O 生成增加，而 NADPH 依赖性 HO 生成减少，并且肥胖大鼠肾脏中的胞质和线粒体 SOD 上调。在肥胖大鼠的肾动脉中，Nox4 下调，Nox4 依赖性 HO 生成和内皮舒张减少。Nox2 和 Nox1 的上调与 O 生成增加但 HO 生成减少和肥胖大鼠内皮 Nox2 衍生的 HO 介导的舒张作用减弱有关。此外，增加的 Nox1 衍生的 O 有助于 OZR 中的肾内皮功能障碍。总之，目前的数据支持 Nox1 衍生的 O 在肥胖中的肾脏血管氧化应激和肾内皮功能障碍中起主要作用，而减少的内皮 Nox4 表达与减少的 HO 生成和 HO 介导的血管舒张有关，这可能会阻碍 Nox4 的肾脏保护作用，从而导致肾脏损伤。这表明，有效的抗氧化应激治疗方法和预防微血管并发症的方法必须确定参与代谢性疾病的特定 Nox 亚基。
