白藜芦醇对脓毒症大鼠急性肾损伤的保护作用及其机制
发布时间：2019-03-16 10:01
【摘要】：脓毒症并发急性肾损伤(AKI)是脓毒症患者死亡率居高不下的重要原因,肾组织炎症因子的瀑布式释放及炎症反应的增强在AKI的发生中起重要作用。核转录因子-κB(NF-κB)是炎症相关基因关键的转录调节因子,活化后可诱导多种炎症因子的转录合成,而内质网应激(ERS)介导了NF-κB炎症信号通路。白藜芦醇是一种具有强大抗炎活性的多酚化合物,其抗炎作用与抑制NF-κB的活性有关,但是是否与缓解ERS有关目前尚无研究报道。因此,本研究旨在以"ERS/NF-κB"通路为切入点,探讨白藜芦醇对脓毒症时急性肾损伤的保护作用及其机制。 本实验首先采用盲肠结扎穿刺术(CLP)建立脓毒症大鼠模型,将108只雄性SD大鼠随机分为A、B、C三大组：A组为生存率观察组,B组为6小时白藜芦醇干预组,C组为12小时白藜芦醇干预组。每组再分为四个小组：(1)假手术组(Sham组)；(2)腹腔注射30mg/kg白藜芦醇的假手术组(Sham+Res组)；(3)脓毒症模型组(CLP组)；(4)腹腔注射30mg/kg白藜芦醇的脓毒症模型组(CLP+Res组)。术后主要观察指标：大鼠的生存情况,肾组织的形态学变化,血肌酐和尿素氮水平,肾脏组织中葡萄糖调节蛋白78(GRP78)/免疫球蛋白重链结合蛋白(BiP)、需肌醇酶(IRE-1)和p65的表达情况；肾组织和血清中TNF-α、IL-1p、IL-6和IL-10的mRNA和蛋白表达水平。 结果显示：(1)以术后72小时为大鼠存活与否的标准,sham组和sham+Res组大鼠的存活率均为100%,CLP组大鼠的存活率约40%,较假手术明显降低(P0.05),而白藜芦醇可显著提高CLP的存活率(P0.05),约65%。(2)术后12小时,CLP组大鼠的血清肌酐和尿素氮水平均较Sham组显著升高(P0.05),白藜芦醇可显著降低CLP血清肌酐和尿素氮的水平(P0.05),但对假手术大鼠无明显影响。此外白藜芦醇可显著减轻CLP大鼠肾小管明显肿胀,管腔变小的表现。(3)术后12小时,白藜芦醇可显著降低CLP大鼠肾组织中GRP78/Bip、磷酸化IRE-1和p65蛋白的高表达(P0.05)。Sham组和Sham+Res组p65主要定位于细胞浆,CLP组p65主要定位于细胞核,而白藜芦醇处理的CLP大鼠p65的细胞定位以胞浆为主。(4)术后6、12小时,白藜芦醇均可显著降低CLP大鼠肾组织中TNF-α、IL-1β、IL-6mRNA的高表达(P0.05),但其对CLP大鼠肾组织中IL-10mRNA的表达均无明显影响(p0.05)。(5)术后6小时,白藜芦醇可显著降低CLP大鼠血清TNF-α、IL-1β和IL-6的含量(P均0.05),但对IL-10含量无明显影响。术后12小时,白藜芦醇不仅显著降低CLP大鼠血清TNF-α、IL-1p和IL-6的含量,且明显增加CLP大鼠血清IL-10含量(P均0.05)。 综上所述,本研究结果表明：白藜芦醇可显著降低脓毒症大鼠的死亡率,减轻急性肾损伤,这可能与其缓解内质网应激,抑制NF-κB通路活化,降低肾组织炎症反应的作用有关。
[Abstract]:(AKI) is an important cause of high mortality in sepsis patients with acute renal injury. Waterfall release of inflammatory factors in renal tissue and enhancement of inflammatory reaction play an important role in the development of AKI. Nuclear transcription factor-魏 B (NF- 魏 B) is a key transcription regulator of inflammation-associated genes. Activation can induce transcription synthesis of a variety of inflammatory factors, while endoplasmic reticulum stress (ERS) mediates NF- 魏 B inflammatory signaling pathway. Resveratrol is a kind of polyphenol compound with strong anti-inflammatory activity. Its anti-inflammatory effect is related to the inhibition of NF- kappa B activity, but there is no report on whether resveratrol is related to the alleviation of ERS. Therefore, the aim of this study was to explore the protective effect of resveratrol on acute renal injury induced by sepsis and the mechanism of resveratrol through "ERS/NF- kappa B" pathway. In this experiment, a rat model of sepsis was established by cecal ligation and puncture (CLP). 108 male SD rats were randomly divided into three groups: group A (survival rate), group B (resveratrol intervention for 6 hours), group A (survival rate) and group B (resveratrol intervention for 6 hours). Group C was treated with resveratrol for 12 hours. Each group was subdivided into four groups: (1) sham operation group (Sham group); (2), sham operation group with 30mg/kg resveratrol injected intraperitoneally, (Sham Res group); (3, sepsis model group (CLP group); (4) 30mg/kg resveratrol model group (CLP Res group). Main outcome measures: survival of rats, morphological changes of renal tissue, levels of serum creatinine and urea nitrogen, glucose-regulated protein 78 (GRP78) / immunoglobulin heavy chain binding protein (BiP), in renal tissue Expression of inositase (IRE-1) and p65; MRNA and protein expression levels of TNF- 伪, IL-1p,IL-6 and IL-10 in kidney and serum. The results showed: (1) the survival rate of rats in sham group and sham Res group was 100% and 40% respectively, which was significantly lower than that in sham operation (P0.05), taking 72 hours after operation as the standard for survival or not of rats, and the survival rates of rats in sham Res group and CLP group were 100% and 40%, respectively (P0.05). Resveratrol significantly increased the survival rate of CLP (P0.05), about 65%. (2) 12 hours after operation, the serum creatinine and urea nitrogen water in CLP group were significantly higher than those in Sham group (P0.05). Resveratrol significantly decreased the levels of serum creatinine and urea nitrogen in CLP (P0.05), but had no significant effect on sham-operated rats. In addition, resveratrol could significantly reduce the swelling of renal tubules and the decrease of lumen in CLP rats. (3) 12 hours after operation, resveratrol significantly decreased GRP78/Bip, in renal tissue of CLP rats. The high expression of phosphorylated IRE-1 and p65 protein (P0.05) was mainly localized in cytoplasm in). Sham group and Sham Res group, while p65 was mainly localized in nucleus in CLP group. (4) 6 hours and 12 hours after operation, resveratrol significantly decreased the high expression of TNF- 伪, IL-1 尾 and IL-6mRNA in renal tissue of CLP rats treated with resveratrol (P0.05). However, resveratrol had no significant effect on the expression of IL-10mRNA in renal tissue of CLP rats (p0.05). (5). Resveratrol significantly decreased the levels of TNF- 伪, IL-1 尾 and IL-6 in serum of CLP rats 6 hours after operation (P0.05). (5), and resveratrol significantly decreased the contents of TNF- 伪, IL-1 尾 and IL-6 in serum of CLP rats. But it had no obvious effect on the content of IL-10. 12 hours after operation, resveratrol not only significantly decreased the levels of serum TNF- 伪, IL-1p and IL-6 in CLP rats, but also significantly increased the content of serum IL-10 in CLP rats (all P0.05). In conclusion, the results showed that resveratrol could significantly reduce the mortality and acute renal injury in sepsis rats, which might be related to the release of endoplasmic reticulum stress and the inhibition of NF- kappa B pathway activation. The effect of reducing the inflammatory reaction of renal tissue is related.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R459.7
本文编号：2441155
[Abstract]:(AKI) is an important cause of high mortality in sepsis patients with acute renal injury. Waterfall release of inflammatory factors in renal tissue and enhancement of inflammatory reaction play an important role in the development of AKI. Nuclear transcription factor-魏 B (NF- 魏 B) is a key transcription regulator of inflammation-associated genes. Activation can induce transcription synthesis of a variety of inflammatory factors, while endoplasmic reticulum stress (ERS) mediates NF- 魏 B inflammatory signaling pathway. Resveratrol is a kind of polyphenol compound with strong anti-inflammatory activity. Its anti-inflammatory effect is related to the inhibition of NF- kappa B activity, but there is no report on whether resveratrol is related to the alleviation of ERS. Therefore, the aim of this study was to explore the protective effect of resveratrol on acute renal injury induced by sepsis and the mechanism of resveratrol through "ERS/NF- kappa B" pathway. In this experiment, a rat model of sepsis was established by cecal ligation and puncture (CLP). 108 male SD rats were randomly divided into three groups: group A (survival rate), group B (resveratrol intervention for 6 hours), group A (survival rate) and group B (resveratrol intervention for 6 hours). Group C was treated with resveratrol for 12 hours. Each group was subdivided into four groups: (1) sham operation group (Sham group); (2), sham operation group with 30mg/kg resveratrol injected intraperitoneally, (Sham Res group); (3, sepsis model group (CLP group); (4) 30mg/kg resveratrol model group (CLP Res group). Main outcome measures: survival of rats, morphological changes of renal tissue, levels of serum creatinine and urea nitrogen, glucose-regulated protein 78 (GRP78) / immunoglobulin heavy chain binding protein (BiP), in renal tissue Expression of inositase (IRE-1) and p65; MRNA and protein expression levels of TNF- 伪, IL-1p,IL-6 and IL-10 in kidney and serum. The results showed: (1) the survival rate of rats in sham group and sham Res group was 100% and 40% respectively, which was significantly lower than that in sham operation (P0.05), taking 72 hours after operation as the standard for survival or not of rats, and the survival rates of rats in sham Res group and CLP group were 100% and 40%, respectively (P0.05). Resveratrol significantly increased the survival rate of CLP (P0.05), about 65%. (2) 12 hours after operation, the serum creatinine and urea nitrogen water in CLP group were significantly higher than those in Sham group (P0.05). Resveratrol significantly decreased the levels of serum creatinine and urea nitrogen in CLP (P0.05), but had no significant effect on sham-operated rats. In addition, resveratrol could significantly reduce the swelling of renal tubules and the decrease of lumen in CLP rats. (3) 12 hours after operation, resveratrol significantly decreased GRP78/Bip, in renal tissue of CLP rats. The high expression of phosphorylated IRE-1 and p65 protein (P0.05) was mainly localized in cytoplasm in). Sham group and Sham Res group, while p65 was mainly localized in nucleus in CLP group. (4) 6 hours and 12 hours after operation, resveratrol significantly decreased the high expression of TNF- 伪, IL-1 尾 and IL-6mRNA in renal tissue of CLP rats treated with resveratrol (P0.05). However, resveratrol had no significant effect on the expression of IL-10mRNA in renal tissue of CLP rats (p0.05). (5). Resveratrol significantly decreased the levels of TNF- 伪, IL-1 尾 and IL-6 in serum of CLP rats 6 hours after operation (P0.05). (5), and resveratrol significantly decreased the contents of TNF- 伪, IL-1 尾 and IL-6 in serum of CLP rats. But it had no obvious effect on the content of IL-10. 12 hours after operation, resveratrol not only significantly decreased the levels of serum TNF- 伪, IL-1p and IL-6 in CLP rats, but also significantly increased the content of serum IL-10 in CLP rats (all P0.05). In conclusion, the results showed that resveratrol could significantly reduce the mortality and acute renal injury in sepsis rats, which might be related to the release of endoplasmic reticulum stress and the inhibition of NF- kappa B pathway activation. The effect of reducing the inflammatory reaction of renal tissue is related.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R459.7
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