Autophagy activation reduces renal tubular injury induced by urinary proteins.
Autophagy activation reduces renal tubular injury induced by urinary proteins.
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DOI：
10.4161/auto.27004
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发表时间：
2014-02
期刊：
影响因子：
13.3
通讯作者：
Liu HF
中科院分区：
文献类型：
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作者：
Liu WJ;Luo MN;Tan J;Chen W;Huang LZ;Yang C;Pan Q;Li B;Liu HF
自噬被证明对肾毒性药物引起的肾小管损伤是有益的。为了探讨自噬是否能保护肾小管上皮细胞（TECs）免受尿蛋白诱导的损伤，我们在体内外研究了尿蛋白超负荷后TECs自噬的活性和作用。我们发现微小病变型肾病综合征（MCNS）患者和阳离子BSA诱导的严重蛋白尿大鼠模型的TEC中自噬空泡增加。在HK-2细胞中，暴露于从MCNS患者提取的尿蛋白导致自噬体和自溶酶体形成显著增加，SQSTM 1/p62蛋白水平降低。此外，尿蛋白还诱导LC 3-II的溶酶体周转和溶酶体的核周聚集。这些变化是由活性氧（ROS）依赖性机制介导的。此外，雷帕霉素预处理HK-2细胞减少了LCN 2/NGAL和HAVCR 1/KIM-1的产生以及尿蛋白诱导的细胞凋亡水平。相反，用氯喹或BECN 1 siRNA阻断自噬产生相反的效果。在用雷帕霉素和氯喹治疗后的蛋白尿动物模型中也观察到类似的结果。两者合计，我们的研究结果表明，自噬通量的增加，安装后尿蛋白超载TECs的适应性反应。
Autophagy is shown to be beneficial for renal tubular injury caused by nephrotoxic drugs. To investigate whether autophagy could protect renal tubular epithelial cells (TECs) from injury induced by urinary proteins, we studied the activity and action of autophagy in TECs after urinary protein overload in vivo and in vitro. We found that autophagic vacuoles increased in TECs from patients with minimal change nephrotic syndrome (MCNS) and rat models with severe proteinuria induced by cationic BSA. In HK-2 cells, exposure to urinary proteins extracted from patients with MCNS led to a significant increase in autophagosome and autolysosome formation and decrease in SQSTM1/p62 protein level. Urinary protein addition also induced lysosomal turnover of LC3-II and perinuclear clustering of lysosomes. These changes were mediated by a reactive oxygen species (ROS)-dependent mechanism. Furthermore, pretreatment of HK-2 cells with rapamycin reduced the production of LCN2/NGAL and HAVCR1/KIM-1 and the level of apoptosis induced by urinary proteins. In contrast, blocking autophagy with chloroquine or BECN1 siRNAs exerted an opposite effect. Similar results were also observed in animal models with proteinuria after treatments with rapamycin and chloroquine. Taken together, our results indicated an increase in autophagic flux, which mounts an adaptive response in TECs after urinary protein overload.