Departmento de Cuidados Intensivos, Hospital Universitario de Getafe, Madrid, Spain.
Shock. 2012 Oct;38(4):403-10. doi: 10.1097/SHK.0b013e31826660f2.
The mechanisms involved in sepsis-induced acute kidney injury (AKI) are unknown. We investigated the role of nitrosative stress in sepsis-induced AKI by studying the effects of manganese (III) tetrakis-(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), a peroxynitrite decomposition catalyst, and aminoguanidine (AG), a selective nitric oxide synthase 2 (NOS2) inhibitor and peroxynitrite scavenger, on kidney function of rats subjected to cecal ligation and puncture (CLP). Sprague-Dawley rats (weighing 350 [SD, 50] g) were treated with MnTMPyP (6 mg/kg i.p.) or AG (50 mg/kg i.p.) at t = 12 and 24 h after CLP or sham procedure. At t = 36 h, mean arterial pressure and aortic blood flow were measured, and blood and urine samples were obtained for biochemical determinations, including creatinine clearance, fractional excretion of sodium, and neutrophil gelatinase-associated lipocalin concentration in the urine. Kidney tissue samples were obtained for (i) light microscopy, (ii) immunofluorescence and Western blot for 3-nitrotyrosine and NOS2, (iii) gene expression (quantitative real-time polymerase chain reaction) studies (NOS1, NOS2, NOS3, and superoxide dismutase 1), and (iv) matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Mean arterial pressure was unchanged and aortic blood flow decreased 25% in CLP animals. The sepsis-induced (i) decreased urine output and creatinine clearance and increased fractional excretion of sodium and urinary neutrophil gelatinase-associated lipocalin concentration, (ii) increased protein nitration and NOS2 protein, and (iii) NOS1 and NOS2 upregulation were all significantly attenuated by treatment with MnTMPyP or AG. Nitrated proteins in renal tissue from CLP animals (matrix-assisted laser desorption ionization time-of-flight mass spectrometry) were glutamate dehydrogenase, methylmalonate-semialdehyde dehydrogenase, and aldehyde dehydrogenase, mitochondrial proteins involved in energy metabolism or antioxidant defense. Nitro-oxidative stress is involved in sepsis-induced AKI, and protein nitration seems to be one mechanism involved.
脓毒症诱导急性肾损伤（AKI）的机制尚不清楚。我们通过研究过氧亚硝酸盐分解催化剂锰（III）四（1-甲基-4-吡啶）卟啉五氯（MnTMPyP）和选择性一氧化氮合酶 2（NOS2）抑制剂和过氧亚硝酸盐清除剂氨基胍（AG）对盲肠结扎和穿刺（CLP）后大鼠肾功能的影响，研究了硝化应激在脓毒症诱导的 AKI 中的作用。Sprague-Dawley 大鼠（体重 350 [SD，50] g）在 CLP 或假手术 12 和 24 小时后用 MnTMPyP（6 mg/kg ip）或 AG（50 mg/kg ip）治疗。在 t = 36 h 时，测量平均动脉压和主动脉血流量，并采集血和尿样进行生化测定，包括肌酐清除率、钠排泄分数和尿中性粒细胞明胶酶相关脂质运载蛋白浓度。获得肾组织样本进行（i）光镜检查、（ii）免疫荧光和 3-硝基酪氨酸和 NOS2 的 Western blot、（iii）基因表达（定量实时聚合酶链反应）研究（NOS1、NOS2、NOS3 和超氧化物歧化酶 1）和（iv）基质辅助激光解吸电离飞行时间质谱。CLP 动物的平均动脉压保持不变，主动脉血流量下降 25%。脓毒症诱导的（i）尿输出减少和肌酐清除率降低，钠排泄分数和尿中性粒细胞明胶酶相关脂质运载蛋白浓度增加，（ii）蛋白质硝化和 NOS2 蛋白增加，以及（iii）NOS1 和 NOS2 的上调均被 MnTMPyP 或 AG 治疗显著减弱。CLP 动物肾组织中的硝化蛋白（基质辅助激光解吸电离飞行时间质谱）是谷氨酸脱氢酶、甲基丙二醛半醛脱氢酶和醛脱氢酶，这些蛋白参与能量代谢或抗氧化防御的线粒体蛋白。硝化氧化应激参与脓毒症诱导的 AKI，蛋白质硝化似乎是一种参与机制。
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