Aldehyde dehydrogenase 2 regulates autophagy via the Akt-mTOR pathway to mitigate renal ischemia-reperfusion injury in hypothermic machine perfusion
Aldehyde dehydrogenase 2 regulates autophagy via the Akt-mTOR pathway to mitigate renal ischemia-reperfusion injury in hypothermic machine perfusion
复制标题
醛脱氢酶 2 通过 Akt-mTOR 通路调节自噬减轻低温机器灌注中肾缺血再灌注损伤
DOI：
10.1016/j.lfs.2020.117705
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发表时间：
2020-07-15
期刊：
影响因子：
6.1
通讯作者：
Ye, Qifa
中科院分区：
文献类型：
--
作者：
Lin, Danni;Xiang, Tao;Ye, Qifa
目的：缺血再灌注损伤（IRI）对肾移植后的患者有害。低温机器灌注（HMP）可用于保存移植物并减少继发性损伤。我们假设醛脱氢酶2（ALDH2）通过调节HMP中的过度自噬部分减轻肾脏IRI。
材料和方法：将兔子分为5组：正常组、HMP组、HMP + Alda - 1组、HMP + CYA组和冷储存（CS）组。在兔自体肾移植后，通过组织学分析、肾小球相关蛋白（结蛋白、 nephrin）、肾小管损伤因子（NGAL、Ki67）、血清肌酐（Cr）和血尿素氮（BUN）评估肾脏病理和功能。通过免疫组织化学评估氧化应激分子丙二醛（MDA）和超氧化物歧化酶（SOD2）的表达以及炎症细胞因子（TNF -α、IL - 6、IL - 10）。通过免疫组织化学、RT - PCR、蛋白质印迹分析或ELISA测量LC3、p62、ALDH2、p - Akt、mTOR、PTEN、p - PTEN和4 - HNE的表达。
主要发现：HMP在肾脏保存方面比CS更有效，HMP中p - ALDH2的表达量更大。HMP + Alda - 1组的肾脏病理和功能结果最佳。HMP + CYA组的MDA和SOD2以及维亚切斯拉夫评分得到改善。ALDH2减轻了4 - HNE诱导的氧化应激、炎症浸润、LC3和p62的表达，并通过p - PTEN/PTEN抑制自噬，同时激活pAkt和mTOR。
意义：Akt - mTOR自噬途径是ALDH2的一个新靶点，通过在HMP中抑制4 - HNE部分减轻肾脏IRI，从而保护心脏死亡后捐献的肾脏（DCD）。
Aims: Ischemia-reperfusion injury (IRI) is harmful to patients following kidney transplantation. Hypothermic machine perfusion (HMP) can be adopted to preserve grafts and reduce consequential injury. We hypothesized that aldehyde dehydrogenase 2 (ALDH2) partly mitigates kidney IRI via regulating excessive autophagy in HMP.Materials and methods: The rabbits were assigned to 5 groups: Normal, HMP, HMP + Alda-1, HMP + CYA and cold storage (CS). After the rabbit autologous kidney transplantation, renal pathology and function were evaluated by histological analysis, glomerular related proteins (desmin, nephrin), tubular injury factors (NGAL, Ki67), serum creatinine (Cr) and blood urea nitrogen (BUN). Oxidative stress molecular Malondialdehyde (MDA) and superoxide dismutase (SOD2) expression, as well as inflammatory cytokines (TNF-alpha, IL-6, IL-10) were assessed by immunohistochemistry. The expression of LC3, p62, ALDH2, p-Akt, mTOR, PTEN, p-PTEN, and 4-HNE were measured by immunohistochemistry, RT-PCR, Western blot analysis or ELISA.Key findings: HMP was more effective than CS for kidney preservation, with p-ALDH2 expressed in greater quantities in HMP. The results of kidney pathology and function in HMP + Alda-1 were the best. The MDA & SOD2 and the Vyacheslav score were improved in HMP+ CYA. ALDH2 reduced 4-HNE-induced oxidative stress, inflammatory infiltration, the expression of LC3, p62 and inhibited autophagy accompanied by activation of pAkt and mTOR via p-PTEN/PTEN.Significance: Akt-mTOR autophagy pathway is a novel target for ALDH2 to reduce renal IRI partly by inhibition of 4-HNE in HMP, then protecting the donated kidney received after cardiac death (DCD).