Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway.
Impaired ATG16L-Dependent Autophagy Promotes Renal Interstitial Fibrosis in Chronic Renal Graft Dysfunction Through Inducing EndMT by NF-κB Signal Pathway.
复制标题
ATG16L 依赖性自噬受损通过 NF-kappa B 信号通路诱导 EndMT 促进慢性肾移植功能障碍中的肾间质纤维化
DOI：
10.3389/fimmu.2021.650424
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tan R
中科院分区：
文献类型：
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作者：
Gui Z;Suo C;Wang Z;Zheng M;Fei S;Chen H;Sun L;Han Z;Tao J;Ju X;Yang H;Gu M;Tan R
慢性移植肾功能不全（CAD）是由多种因素引起的，包括肾小球硬化、炎症、间质纤维化和肾小管萎缩（IF/TA）。然而，CAD最突出的元素是IF/TA。我们的研究已经证实内皮-间质转化（EndMT）是同种异体IF/TA的重要来源。EndMT的特点是内皮标志物的丢失和间充质或成纤维细胞表型的获得。自噬是一种由自噬相关蛋白调控的细胞内降解途径，在许多纤维化疾病中起着重要作用。然而，自噬是否参与了移植肾纤维化以及其机制尚不清楚。自噬相关16样基因（ATG 16 L）是自噬体形成所必需的一个重要的自噬相关基因（ARG）。在这里，我们首先分析了来自基因表达综合数据集（GEO）的肾移植患者组织和来自我们中心的60名移植患者。肾功能稳定者为非CAD组，CAD组所有患者均经组织病理学确诊为CAD。结果显示，ATG 16 L作为一种显著差异的ARG，在CAD组中的表达低于非CAD组。此外，我们发现CAD患者移植肾中自噬体和自溶酶体较少，自噬下调是一个不良的预后因素。在体外实验中，我们发现ATG 16 L的敲低增强了人肾小球内皮细胞（HRGECs）中EndMT的过程。在体内，检测CAD大鼠肾移植模型中EndMT和自噬流量的变化。我们证实了EndMT的发生，并指出ATG 16 L的丰富伴随着肾移植沿着不同阶段的动态自噬流量变化。在机制上，ATG 16 L的敲低，特别是在内皮细胞中，减少NF-κB降解和分泌炎性细胞因子（IL-1β、IL-6和TNF-α），这可以促进EndMT。总之，由移植引起的ATG 16 L依赖性自噬通量显示出随时间推移的进行性损失增加。来自该过程的炎性细胞因子促进EndMT，从而导致CAD的进展。ATG 16 L作为EndMT和肾移植物纤维化发展的负调节剂，自噬可以被探索为慢性肾移植物功能障碍的潜在治疗靶点。
Chronic renal graft dysfunction (CAD) is caused by multiple factors, including glomerular sclerosis, inflammation, interstitial fibrosis and tubular atrophy (IF/TA). However, the most prominent elements of CAD are IF/TA. Our studies have confirmed that endothelial-mesenchymal transition (EndMT) is an important source to allograft IF/TA. The characteristic of EndMT is the loss of endothelial marker and the acquisition of mesenchymal or fibroblastic phenotypes. Autophagy is an intracellular degradation pathway that is regulated by autophagy-related proteins and plays a vital role in many fibrotic conditions. However, whether or not autophagy contributes to fibrosis of renal allograft and how such mechanism occurs still remains unclear. Autophagy related 16 like gene (ATG16L) is a critical autophagy-related gene (ARG) necessary for autophagosome formation. Here, we first analyzed kidney transplant patient tissues from Gene Expression Omnibus (GEO) datasets and 60 transplant patients from our center. Recipients with stable kidney function were defined as non-CAD group and all patients in CAD group were histopathologically diagnosed with CAD. Results showed that ATG16L, as one significant differential ARG, was less expressed in CAD group compared to the non-CAD group. Furthermore, we found there were less autophagosomes and autolysosomes in transplanted kidneys of CAD patients, and downregulation of autophagy is a poor prognostic factor. In vitro, we found out that the knockdown of ATG16L enhanced the process of EndMT in human renal glomerular endothelial cells (HRGECs). In vivo, the changes of EndMT and autophagic flux were then detected in rat renal transplant models of CAD. We demonstrated the occurrence of EndMT, and indicated that abundance of ATG16L was accompanied by the dynamic autophagic flux change along different stages of kidney transplantation. Mechanistically, knockdown of ATG16L, specifically in endothelial cells, reduced of NF-κB degradation and excreted inflammatory cytokines (IL-1β, IL-6 and TNF-α), which could facilitate EndMT. In conclusion, ATG16L-dependent autophagic flux causing by transplant showed progressive loss increase over time. Inflammatory cytokines from this process promoted EndMT, thereby leading to progression of CAD. ATG16L served as a negative regulator of EndMT and development of renal graft fibrosis, and autophagy can be explored as a potential therapeutic target for chronic renal graft dysfunction.