醛糖还原酶抑制可抵消糖尿病大鼠肾脏和高糖培养的人系膜细胞中的亚硝化应激及聚（ADP - 核糖）聚合酶激活。
Aldose reductase inhibition counteracts nitrosative stress and poly(ADP-ribose) polymerase activation in diabetic rat kidney and high-glucose-exposed human mesangial cells.
作者信息
Drel Viktor R, Pacher Pal, Stevens Martin J, Obrosova Irina G
机构信息
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, 70808, USA.
出版信息
Free Radic Biol Med. 2006 Apr 15;40(8):1454-65. doi: 10.1016/j.freeradbiomed.2005.12.034. Epub 2006 Jan 31.
Both increased aldose reductase (AR) activity and oxidative/nitrosative stress have been implicated in the pathogenesis of diabetic nephropathy, but the relation between the two factors remains a subject of debate. This study evaluated the effects of AR inhibition on nitrosative stress and poly(ADP-ribose) polymerase (PARP) activation in diabetic rat kidney and high-glucose-exposed human mesangial cells. In animal experiments, control (C) and streptozotocin-diabetic (D) rats were treated with/without the AR inhibitor fidarestat (F, 16 mg kg(-1) day(-1)) for 6 weeks starting from induction of diabetes. Glucose, sorbitol, and fructose concentrations were significantly increased in the renal cortex of D vs C (p < 0.01 for all three comparisons), and sorbitol pathway intermediate, but not glucose, accumulation, was completely prevented in D + F. F at least partially prevented diabetes-induced increase in kidney weight as well as nitrotyrosine (NT, a marker of peroxynitrite-induced injury and nitrosative stress), and poly(ADP-ribose) (a marker of PARP activation) accumulation, assessed by both immunohistochemistry and Western blot analysis, in glomerular and tubular compartments of the renal cortex. In vitro studies revealed the presence of both AR and PARP-1 in human mesangial cells, and none of these two variables were affected by high glucose or F treatment. Nitrosylated and poly(ADP-ribosyl)ated proteins (Western blot analysis) accumulated in cells cultured in 30 mM D-glucose (vs 5.55 mM glucose, p < 0.01), but not in cells cultured in 30 mM L-glucose or 30 mM D-glucose plus 10 microM F. AR inhibition counteracts nitrosative stress and PARP activation in the diabetic renal cortex and high-glucose-exposed human mesangial cells. These findings reveal new beneficial properties of the AR inhibitor F and provide the rationale for detailed studies of F on diabetic nephropathy.
醛糖还原酶（AR）活性增加和氧化/亚硝化应激均与糖尿病肾病的发病机制有关，但这两个因素之间的关系仍存在争议。本研究评估了AR抑制对糖尿病大鼠肾脏和高糖暴露的人系膜细胞中亚硝化应激和聚（ADP-核糖）聚合酶（PARP）激活的影响。在动物实验中，从糖尿病诱导开始，对照（C）大鼠和链脲佐菌素诱导的糖尿病（D）大鼠接受或不接受AR抑制剂非达司他（F，16 mg·kg⁻¹·天⁻¹）治疗6周。与C组相比，D组肾皮质中的葡萄糖、山梨醇和果糖浓度显著升高（所有三项比较p < 0.01），并且在D + F组中完全阻止了山梨醇途径中间体（而非葡萄糖）的积累。通过免疫组织化学和蛋白质印迹分析评估，F至少部分阻止了糖尿病诱导的肾脏重量增加以及肾皮质肾小球和肾小管区域中硝基酪氨酸（NT，过氧亚硝酸盐诱导损伤和亚硝化应激的标志物）和聚（ADP-核糖）（PARP激活的标志物）的积累。体外研究显示人系膜细胞中存在AR和PARP-1，并且这两个变量均不受高糖或F处理的影响。在30 mM D-葡萄糖（与5.55 mM葡萄糖相比，p < 0.01）中培养的细胞中，亚硝基化和聚（ADP-核糖基）化蛋白（蛋白质印迹分析）积累，但在30 mM L-葡萄糖或30 mM D-葡萄糖加10 μM F中培养的细胞中未积累。AR抑制可抵消糖尿病肾皮质和高糖暴露的人系膜细胞中的亚硝化应激和PARP激活。这些发现揭示了AR抑制剂F的新有益特性，并为详细研究F对糖尿病肾病的作用提供了理论依据。
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