Apocynin attenuates renal fibrosis via inhibition of NOXs-ROS-ERK-myofibroblast accumulation in UUO rats
Apocynin attenuates renal fibrosis via inhibition of NOXs-ROS-ERK-myofibroblast accumulation in UUO rats
复制标题
罗布麻宁通过抑制 UUO 大鼠中 NOXs-ROS-ERK-肌成纤维细胞的积累来减轻肾纤维化
DOI：
10.1080/10715762.2016.1181757
复制
发表时间：
2016-01-01
影响因子：
3.3
通讯作者：
Wang, Yu
中科院分区：
文献类型：
--
作者：
Cheng, Xi;Zheng, Xizi;Wang, Yu
摘要背景：氧化应激已被确定为单侧输尿管梗阻（UUO）肾间质纤维化发展的重要发病机制。先前的研究表明，UUO 会导致烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶 (NOX) 的表达增加。我们的目的是探讨NOXs激活是否通过氧化应激和潜在机制参与UUO肾纤维化的发展。方法：对 Wistar 大鼠进行 UUO 后立即开始灌胃 NOXs 抑制剂罗布麻宁，并持续至 UUO 后 7 天。评估氧化应激、肾巨噬细胞浸润和纤维化、TGF-β1表达、NOXs表达和活性、ERK活化等标志物的变化。结果：罗布麻宁显着减弱 UUO 梗阻肾脏中 NOX 的活性，同时降低 NOX2、NOX4 和氧化应激标志物的表达。此外，夹竹桃麻素治疗可减轻 UUO 引起的胶原沉积和肾纤维化。此外，罗布麻素治疗显着减弱了梗阻肾脏中 ERK 的磷酸化、肌成纤维细胞的积累和巨噬细胞的浸润。没有观察到夹竹桃麻素对 UUO 诱导的 TGF-β1 表达增加的显着影响。罗布麻宁治疗大鼠梗阻肾脏中的抗氧化剂酶活性没有显着变化。结论：这些结果表明，罗布麻素可能通过抑制 UUO 大鼠中 NOX 的活化以及随后减少氧化应激、ERK 活化和肌成纤维细胞积累而对肾纤维化发挥有益作用。靶向NOXs可能作为治疗肾纤维化的一种治疗策略。
Abstract Background: Oxidative stress has been identified as an important pathogenesis mechanism in the development of renal interstitial fibrosis in unilateral ureteral obstruction (UUO). Previous studies have demonstrated increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOXs) in response to UUO. We aimed to investigate whether NOXs activation was involved in the development of renal fibrosis in UUO by contribution to oxidative stress and the potential mechanism in the present study. Methods: Apocynin, a NOXs inhibitor, was initiated immediately by gavage after UUO was performed on Wistar rats and continued until 7 days after UUO. Changes of markers of oxidative stress, renal macrophage infiltration and fibrosis, TGF-β1 expression, NOXs expression and activity, and ERK activation were evaluated. Results: Apocynin significantly attenuated the activity of NOXs, accompanied with decreased expression of NOX2, NOX4, and oxidative stress markers in the obstructed kidneys of UUO. Additionally, collagen deposition and renal fibrosis induced by UUO were attenuated by apocynin treatment. Furthermore, apocynin treatment significantly attenuated the phosphorylation of ERK, accumulation of myofibroblast and infiltration of macrophage in obstructed kidneys. No significant effect of apocynin on UUO-induced increased TGF-β1 expression could be observed. And there was no significant change of anti-oxidants enzyme activities in the obstructed kidneys of apocynin-treated rats. Conclusions: These results suggested that apocynin might exert beneficial effects on renal fibrosis by inhibition of NOXs activation and subsequent reduction of oxidative stress, ERK activation, and myofibroblast accumulation in UUO rats. Targeting NOXs may serve as a therapeutic strategy for the treatment of renal fibrosis.