Effects of autophagy on kidney injury induce aristolo chic and its influencing factors

Yan FENG; Jiaruo XU; Tingting LIN; Guangtao YAO; Jialiang CHEN

doi:10.16306/j.1008-861x.2022.02.011

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Effects of autophagy on kidney injury induce aristolo chic and its influencing factors

Experiment Research | 更新时间：2022-08-29

- Effects of autophagy on kidney injury induce aristolo chic and its influencing factors
- Academic Journal of Shanghai University of Traditional Chinese Medicine Vol. 36, Issue 2, Pages: 68-75(2022)
- 作者机构：
  
  1.上海中医药大学附属曙光医院（上海　201203）
  2.上海中医药大学（上海　201203）
- 作者简介：
- 基金信息：
- DOI：10.16306/j.1008-861x.2022.02.011
  CLC：
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冯燕,徐嘉若,林婷婷等.自噬在马兜铃酸引起肾损伤过程中的作用及影响因素[J].上海中医药大学学报,2022,36(02):68-75.

FENG Yan,XU Jiaruo,LIN Tingting,et al.Effects of autophagy on kidney injury induce aristolo chic and its influencing factors[J].Academic Journal of Shanghai University of Traditional Chinese Medicine,2022,36(02):68-75.
冯燕,徐嘉若,林婷婷等.自噬在马兜铃酸引起肾损伤过程中的作用及影响因素[J].上海中医药大学学报,2022,36(02):68-75. DOI： 10.16306/j.1008-861x.2022.02.011.

FENG Yan,XU Jiaruo,LIN Tingting,et al.Effects of autophagy on kidney injury induce aristolo chic and its influencing factors[J].Academic Journal of Shanghai University of Traditional Chinese Medicine,2022,36(02):68-75. DOI： 10.16306/j.1008-861x.2022.02.011.

摘要

目的,2,考察自噬在马兜铃酸Ⅰ（AAⅠ）诱导的大鼠肾损伤过程中的作用，并探讨相关影响因素。,方法,2,Wistar大鼠，雄性，随机分为正常组、3-甲基腺嘌呤（3-MA）组、AAⅠ低剂量组（20 mg/kg）、AAⅠ高剂量组（40 mg/kg）、3-MA+AAⅠ低剂量组（以下简称联用低剂量组）、3-MA+AAⅠ高剂量组（以下简称联用高剂量组），每组11只。3-MA组预先腹腔注射20 mg/kg 3-MA。干预1 h后，其余各组腹腔注射相应剂量的AAⅠ，连续9 d。末次给药后，动物腹主动脉取血，分离肾脏。生化分析仪检测血清尿素氮（BUN）、肌酐（CREA）水平；光镜和电镜下观察肾脏组织形态学变化。PCR和免疫组化法检测肾组织Beclin 1、微管相关蛋白轻链3（LC3）、p53 蛋白和mRNA表达水平。,结果,2,①AAⅠ高剂量组较正常组大鼠BUN、CREA均明显升高；联用高剂量组较AAⅠ高剂量组大鼠BUN、CREA均降低，但差异无统计学意义（,P,>,0.05）。②HE染色及透射电镜结果显示，AAⅠ高、低剂量组不同程度细胞肿胀，上皮细胞坏死，胞浆崩解脱落，且高剂量较低剂量组细胞肿胀程度明显加重；联用低剂量组较AAⅠ低剂量组肾小管上皮细胞肿胀，内质网扩张，损伤略有加重；联用高剂量组较AAⅠ高剂量组肾小管上皮细胞脱落、坏死，隐见自噬小体，损伤略有减轻。③AAⅠ高、低剂量组较正常组大鼠肾脏Beclin 1、LC3、p53 蛋白和mRNA表达均明显上调（,P,<,0.05，,P,<,0.01）；联用低剂量组较AAⅠ低剂量组大鼠LC3、p53 蛋白相对表达量均明显下调（,P,<,0.01）；联用高剂量组较AAⅠ高剂量组大鼠肾脏3种基因和蛋白表达均明显下调（,P,<,0.01）。④AAⅠ高剂量组较AAⅠ低剂量组大鼠肾脏,LC3, mRNA和蛋白表达均明显上调（,P,<,0.01），Beclin 1、p53蛋白表达均明显上调（,P,<,0.01）；联用高剂量组较联用低剂量组大鼠肾脏Beclin 1 蛋白和mRNA相对表达量明显下调（,P,<,0.01），LC3、p53 蛋白相对表达量均明显上调（,P,<,0.01）。,结论,2,AAⅠ低剂量引起的肾损伤过程中，可能发生了自噬，且自噬减轻肾脏损伤；AAⅠ高剂量引起的肾损伤过程中，可能发生了过度自噬，且自噬加重肾脏损伤，其作用机制可能与调节p53蛋白表达相关。

Abstract

Objective： To investigate the role of autophagy in aristolochic acid Ⅰ（AAⅠ）-induced kidney injury in rat model and to explore related influencing factors.,Methods,2,Wistar rats， male， were randomly divided into normal group， 3-methyladenine（3-MA）group， AAⅠ low-dose group （20 mg/kg）， AAⅠ high-dose group （40 mg/kg）， 3-MA+AAⅠ low-dose group（hereinafter to be refered as combined low-dose group）and 3-MA+AAⅠ high-dose group （hereinafter to be refered as combined high-dose group）， with eleven rats in each group. The 3-MA group was intraperitoneally injected with 20 mg/kg 3-MA firsthy. After intervened for 1 h， other groups were given the corresponding dose of AAⅠ for 9 days continuously. After the last administration， the blood was collected by abdominal aortic method and the kidney was isolated. The levels of serum urea nitrogen（BUN） and serum creatinine（Scr）were detected by biochemical analyzer. The histopathological morphology changes of kidney were observed by light microscope and electron microscope. PCR and immune-histochemical method were used to detect the expression levels of mRNA and protein of Beclin 1， microtubule-associated protein light chain 3（LC3）and p53 in kidney.,Results,2,①The BUN and Scr levels of the AAⅠ high-dose group were significantly higher than that of the normal group， while the BUN and Scr levels of the combined high-dose group were lower than the AAⅠ high-dose group， but the differences have no statistical significance（,P,>,0.05）. ②The results of HE staining and transmission electron microscopy showed different degrees of cell swelling， epithelial cell necrosis， cytoplasmic disintegration and exfoliation in both the AAⅠ high and low dose groups， and the cell swelling in the high-dose group was obviously more serious than that in the low-dose group. Compared with the AAⅠ low-dose group， the renal tubular epithelial cells were swollen， endoplasmic reticulum was dilated， and the injury was slightly aggravated in the combined low-dose group. Compared with the AAⅠ high-dose group， the renal tubular epithelial cells were exfoliated and necrotic， cytolysosomme was faintly observed， and the damage was slightly alleviated in the combined high-dose group. ③Compared with the normal group， the protein and mRNA expressions of Beclin 1， LC3， p53 in rats’ kidney of both the AAⅠ high and low dose groups were significantly increased（,P,<,0.05， ,P,<,0.01）. Compared with the AAⅠ low-dose group， the relative expressions of LC3 and p53 protein in rats’ kidney of the combined low-dose group were significantly decreased（,P,<,0.01）. Compared with the AAⅠ high-dose group， the expressions of these three genes and proteins in rats’ kidney of the combined high-dose group were significantly decreased（,P,<,0.01）. ④Compared with the AAⅠ low-dose group， the expressions of LC3 on mRNA and protein in the kidney of rats in the AAⅠ high-dose group were significantly increased（,P,<,0.01）， and the expressions of Beclin 1 and p53 protein were significantly increased （,P,<,0.01）. Compared with the combined low-dose group， the protein and mRNA expressions of Beclin 1 in rats’ kidney of the combined high-dose group were significantly decreased（,P,<,0.01）， the relative expressions of LC3 and p53 on protein were significantly increased（,P,<,0.01）.,Conclusions,2,Autophagy may occur in the process of kidney damage induced by low dose of AAⅠ and alleviate kidney damage. Excessive autophagy may occur in the process of kidney damage induced by high dose of AAⅠ and aggravate kidney damage. The mechanism may be relevant to the regulation of p53 protein expression .

关键词

马兜铃酸Ⅰ肾损伤自噬

Keywords

aristolochic acidⅠkidney injuryautophagy

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