Jankauskas S S, Andrianova N V, Alieva I B, Prusov A N, Matsievsky D D, Zorova L D, Pevzner I B, Savchenko E S, Pirogov Y A, Silachev D N, Plotnikov E Y, Zorov D B
Lomonosov Moscow State University, Belozersky Institute of Physico-Chemical Biology, Moscow, 119991, Russia.
Biochemistry (Mosc). 2016 Dec;81(12):1538-1548. doi: 10.1134/S0006297916120154.
One of the most important pathological consequences of renal ischemia/reperfusion (I/R) is kidney malfunctioning. I/R leads to oxidative stress, which affects not only nephron cells but also cells of the vascular wall, especially endothelium, resulting in its damage. Assessment of endothelial damage, its role in pathological changes in organ functioning, and approaches to normalization of endothelial and renal functions are vital problems that need to be resolved. The goal of this study was to examine functional and morphological impairments occurring in the endothelium of renal vessels after I/R and to explore the possibility of alleviation of the severity of these changes using mitochondria-targeted antioxidant 10-(6'-plastoquinonyl)decylrhodamine 19 (SkQR1). Here we demonstrate that 40-min ischemia with 10-min reperfusion results in a profound change in the structure of endothelial cells mitochondria, accompanied by vasoconstriction of renal blood vessels, reduced renal blood flow, and increased number of endothelial cells circulating in the blood. Permeability of the kidney vascular wall increased 48 h after I/R. Injection of SkQR1 improves recovery of renal blood flow and reduces vascular resistance of the kidney in the first minutes of reperfusion; it also reduces the severity of renal insufficiency and normalizes permeability of renal endothelium 48 h after I/R. In in vitro experiments, SkQR1 provided protection of endothelial cells from death provoked by oxygen-glucose deprivation. On the other hand, an inhibitor of NO-synthases, L-nitroarginine, abolished the positive effects of SkQR1 on hemodynamics and protection from renal failure. Thus, dysfunction and death of endothelial cells play an important role in the development of reperfusion injury of renal tissues. Our results indicate that the major pathogenic factors in the endothelial damage are oxidative stress and mitochondrial damage within endothelial cells, while mitochondria-targeted antioxidants could be an effective tool for the protection of tissue from negative effects of ischemia.
肾缺血/再灌注（I/R）最重要的病理后果之一是肾功能障碍。I/R会导致氧化应激，这不仅会影响肾单位细胞，还会影响血管壁细胞，尤其是内皮细胞，导致其受损。评估内皮损伤、其在器官功能病理变化中的作用以及内皮和肾功能正常化的方法是需要解决的重要问题。本研究的目的是检查I/R后肾血管内皮出现的功能和形态损伤，并探索使用线粒体靶向抗氧化剂10-(6'-质体醌基)癸基罗丹明19（SkQR1）减轻这些变化严重程度的可能性。在此我们证明，40分钟缺血加10分钟再灌注会导致内皮细胞线粒体结构发生深刻变化，同时伴有肾血管收缩、肾血流量减少以及血液中循环内皮细胞数量增加。I/R后48小时肾血管壁通透性增加。注射SkQR1可改善肾血流量的恢复，并在再灌注的最初几分钟降低肾脏的血管阻力；它还可减轻肾功能不全的严重程度，并使I/R后48小时肾内皮的通透性恢复正常。在体外实验中，SkQR1可保护内皮细胞免受氧-葡萄糖剥夺引发的死亡。另一方面，一氧化氮合酶抑制剂L-硝基精氨酸消除了SkQR1对血流动力学的积极影响以及对肾衰竭的保护作用。因此，内皮细胞功能障碍和死亡在肾组织再灌注损伤的发展中起重要作用。我们的数据表明，内皮损伤的主要致病因素是氧化应激和内皮细胞内的线粒体损伤，而线粒体靶向抗氧化剂可能是保护组织免受缺血负面影响的有效工具。
