Chade Alejandro R, Rodriguez-Porcel Martin, Herrmann Joerg, Zhu Xiangyang, Grande Joseph P, Napoli Claudio, Lerman Amir, Lerman Lilach O
Department of Internal Medicine, Division of Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
J Am Soc Nephrol. 2004 Apr;15(4):958-66. doi: 10.1097/01.asn.0000117774.83396.e9.
Atherosclerotic renovascular disease (RVD) amplifies damage in a stenotic kidney by inducing pro-inflammatory mechanisms and disrupting tissue remodeling. Oxidative stress is increased in RVD, but its direct contribution to renal injury has not been fully established. The authors hypothesized that chronic antioxidant intervention in RVD would improve renal function and attenuate tissue injury. Single-kidney hemodynamics and function at baseline and during vasoactive challenge were quantified using electron-beam computed tomography in pigs after 12 wk of experimental RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7), RVD daily supplemented with antioxidant vitamins C (1 g), and E (100 IU/kg) (RVD+Vitamins, n = 7), or controls (normal, n = 7). Renal tissue was studied ex vivo using Western blot analysis and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate (GFR) were similarly decreased in the stenotic kidney of both RVD groups. RBF and GFR response to acetylcholine was blunted in RVD, but significantly improved in RVD+Vitamins (P < 0.05 versus RVD). RVD+Vitamins also showed increased renal expression of endothelial nitric oxide synthase (eNOS) and decreased expression of NAD(P)H-oxidase, nitrotyrosine, inducible-NOS, and NF-kappaB, suggesting decreased superoxide abundance and inflammation. Furthermore, decreased expression of pro-fibrotic factors in RVD+Vitamins was accompanied by augmented expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems, resulting in significantly attenuated glomerulosclerosis and renal fibrosis. In conclusion, chronic antioxidant intervention in early experimental RVD improved renal functional responses, enhanced tissue remodeling, and decreased structural injury. This study supports critical pathogenic contribution of increased oxidative stress to renal injury and scarring in RVD and suggests a role for antioxidant strategies in preserving the atherosclerotic and ischemic kidney.
动脉粥样硬化性肾血管疾病（RVD）通过诱导促炎机制和破坏组织重塑，加剧狭窄肾脏的损伤。RVD中氧化应激增加，但其对肾损伤的直接作用尚未完全明确。作者推测，对RVD进行慢性抗氧化干预可改善肾功能并减轻组织损伤。在实验性RVD（通过同时存在的高胆固醇血症和肾动脉狭窄模拟，n = 7）、每日补充抗氧化维生素C（1 g）和维生素E（100 IU/kg）的RVD（RVD+维生素组，n = 7）或对照组（正常组，n = 7）的猪中，在12周后，使用电子束计算机断层扫描对基线和血管活性刺激期间的单肾血流动力学和功能进行定量分析。使用蛋白质印迹分析和免疫组织化学对肾组织进行离体研究。两个RVD组狭窄肾脏的基础肾血流量（RBF）和肾小球滤过率（GFR）均同样降低。RVD组中RBF和GFR对乙酰胆碱的反应减弱，但在RVD+维生素组中显著改善（与RVD组相比，P < 0.05）。RVD+维生素组还显示肾内皮型一氧化氮合酶（eNOS）表达增加，而烟酰胺腺嘌呤二核苷酸磷酸（NAD(P)H）氧化酶、硝基酪氨酸、诱导型一氧化氮合酶和核因子κB的表达降低，提示超氧化物丰度和炎症减少。此外，RVD+维生素组中促纤维化因子表达降低，同时细胞外（基质金属蛋白酶-2）和细胞内（泛素）蛋白质降解系统表达增加，导致肾小球硬化和肾纤维化显著减轻。总之，在早期实验性RVD中进行慢性抗氧化干预可改善肾功能反应，增强组织重塑，并减少结构损伤。本研究支持氧化应激增加对RVD中肾损伤和瘢痕形成的关键致病作用，并提示抗氧化策略在保护动脉粥样硬化和缺血性肾脏方面的作用。
