AMPK/mTOR信号通路在急性肾损伤诱导的急性肺损伤中的作用机制
The Mechanism of Adenosine Monophosphate Activated Protein Kinase/Mammalian Target of the Rapamycin Signaling Pathway in the Acute Kidney Injury-Induced Acute Lung Injury
简禄勇 1袁琦 1曹海虹 1张星炜 1黄仁发1
作者信息
- 1. 广州中医药大学第六临床医学院(广州中医药大学深圳医院)肾病科 (深圳 518034)
- 折叠
摘要
目的:探讨自噬相关的AMPK/mTOR信号通路对急性肾损伤(acute kidney injury,AKI)诱导的急性肺损伤(a-cute lung injury,ALI)的影响及作用机制.方法:48 只雄性SD大鼠随机分为 4 组(n=12):假手术组(sham组),缺血-再灌注损伤组(ischemia-reperfusion injury,IRI组),IRI+雷帕霉素组(rapamycin,RA组),IRI+3-甲基腺嘌呤(3-methylade-nine,3-MA组).进行右侧侧腹切口,结扎并切除右肾.左肾经受60 min的缺血,然后再灌注12、24、48 和72 h.测定血清肌酐、血尿素氮、肺湿/干比、炎症指标和氧化应激水平,对肺、肾进行病理学检测.通过免疫组织化学和蛋白质印迹法检测AMPK、mTOR、p62、LC3-Ⅱ/LC3-Ⅰ比值、Beclin-1、ULK1 的蛋白表达.结果:与sham组大鼠相比,IRI组大鼠在AKI后表现出显著的肺损伤,血清肌酐、血尿素氮、肺湿/干比、炎症指标和氧化应激水平增加(P<0.05).AMPK、LC3-Ⅱ/LC3-Ⅰ比值、Beclin-1、ULK1 的表达增加(P<0.05),而p62 和mTOR减少(P<0.01).此外,RA处理通过激活AMPK/mTOR通路促进自噬显著减轻肺损伤,而3-MA处理通过抑制AMPK/mTOR通路而抑制自噬使肺损伤加重.结论:肾脏IRI后可激活AMPK/mTOR信号通路,并通过该通路诱导自噬,抑制炎症反应、氧化应激和细胞凋亡,从而显著减轻AKI和AKI诱导的ALI.
Abstract
Objective:To investigate the effects of autophagy-related AMPK/mTOR signaling pathway on acute kidney in-jury(AKI)-induced acute lung injury(ALI)and its mechanism.Methods:The 48 male Sprague-Dawley rats were divided into four groups randomly(n=12):(1)sham,(2)ischemia-reperfusion injury(IRI),(3)IRI+rapamycin(RA),and(4)IRI+3-methyladenine(3-MA).Unilateral flank incision was made and right kidney was ligated and excised.The left kidney was subjec-ted to 60 min of ischemia followed by 12,24,48,and 72 h of reperfusion.The levels of Scr,blood urea nitrogen(BUN),lung of Wet/Dry ratio,indexes of inflammation,and oxidative stress were assayed.Histological examinations of lung and kidney were per-formed.The protein expression of AMPK,mTOR,p62,LC3-Ⅱ/LC3-Ⅰ ratio,and Beclin-1,ULK1 was evaluated by western blotting and immunohistochemistry.Results:Compared to the rats from the sham group,IRI rats showed significantly pulmonary dam-age after AKI with increased Scr,BUN,lung of Wet/Dry ratio,indexes of inflammation,and oxidative stress(P＜0.05).The ex-pression of AMPK,LC3-Ⅱ/LC3-Ⅰratio,Beclin-1,and ULK1 and were increased(P＜0.05),while p62 and mTOR were de-creased(P＜0.01).In addition,RA treatment significantly attenuated lung injury by promoting autophagy through the activation of the AMPK/mTOR signaling pathway,and 3-MA treatment exhibited adverse effects inversely.Conclusion:Renal IRI could activate AMPK/mTOR signaling pathway and induce autophagy through this pathway,inhibit inflammatory response,oxidative stress and ap-optosis,thereby significantly alienate AKI and AKI-induced ALI.
关键词
AMPK/mTOR信号通路/肾缺血-再灌注/急性肾损伤/急性肺损伤/自噬/细胞凋亡Key words
AMPK/mTOR signaling pathway/Renal ischemic-reperfusion/Acute kidney injury/Acute lung injury/Autophagy/Apoptosis引用本文复制引用
基金项目
广东省自然科学基金资助项目(2020A1515010566)
深圳市科技研发基金资助项目(JCYJ20190809102413156)
出版年
2024
NETL
NSTL
万方数据