p62/SQSTM1 protects against cisplatin-induced oxidative stress in kidneys by mediating the cross talk between autophagy and the Keap1-Nrf2 signalling pathway
p62/SQSTM1 protects against cisplatin-induced oxidative stress in kidneys by mediating the cross talk between autophagy and the Keap1-Nrf2 signalling pathway
复制标题
p62/SQSTM1 通过介导自噬和 Keap1-Nrf2 信号通路之间的串扰来保护肾脏免受顺铂诱导的氧化应激
DOI：
10.1080/10715762.2019.1635251
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发表时间：
2019-07-03
影响因子：
3.3
通讯作者：
Zhang, Wen
中科院分区：
文献类型：
--
作者：
Liao, Weitang;Wang, Zhiyu;Zhang, Wen
摘要 急性肾损伤（AKI）是一种与临床预后不良相关的主要肾脏疾病。氧化应激主要参与 AKI 的发病机制。自噬和 Keap1-Nrf2 信号通路均参与氧化应激反应。然而，AKI 中这两条通路之间的交互作用仍然未知。在这里，我们发现顺铂诱导的 AKI 期间自噬上调。与之前的研究相比，我们观察到 p62 显着增加。我们还发现 p62 敲低会减少自噬体的形成和 LC3II 的表达。为了探索 p62 和 Keap1-Nrf2 信号通路之间的串扰，用靶向 Nrf2 的 siRNA 转染 HK-2 细胞，我们发现 Nrf2 敲低显着降低了顺铂诱导的 p62 表达。此外，p62敲除显着降低了Nrf2以及血红素加氧酶-1（HO-1）和NAD（P）H：醌氧化还原酶1（NQO1）的蛋白表达，而kelch样ECH相关蛋白1（Keap1）的表达上调。这些结果表明 p62 在 Keap1-Nrf2 信号通路中创建正反馈环。最后，我们检查了p62在顺铂诱导的氧化应激期间细胞保护中的作用，发现HK-2细胞中p62沉默会增加细胞凋亡和活性氧（ROS）水平，这进一步表明p62在氧化应激下的保护作用，并表明62介导的细胞保护部分是通过调节自噬活性或Keap1-Nrf2信号通路来实现的。综上所述，我们的结果证明了氧化应激下 p62、自噬和 Keap1-Nrf2 信号通路的相互调节，这可能是 AKI 的潜在治疗靶点。
Abstract Acute kidney injury (AKI) is a major kidney disease associated with poor clinical outcomes. Oxidative stress is predominantly involved in the pathogenesis of AKI. Autophagy and the Keap1-Nrf2 signalling pathway are both involved in the oxidative-stress response. However, the cross talk between these two pathways in AKI remains unknown. Here, we found that autophagy is upregulated during cisplatin-induced AKI. In contrast with previous studies, we observed a marked increase in p62. We also found that p62 knockdown reduces autophagosome formation and the expression of LC3II. To explore the cross talk between p62 and the Keap1-Nrf2 signalling pathway, HK-2 cells were transfected with siRNA targeting Nrf2, and we found that Nrf2 knockdown significantly reduced cisplatin-induced p62 expression. Moreover, p62 knockdown significantly decreased the protein expression of Nrf2, as well as Heme Oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase l (NQO1), whereas the expression of kelch-like ECH-associated protein 1 (Keap1) was upregulated. These results indicate that p62 creates a positive feedback loop in the Keap1-Nrf2 signalling pathway. Finally, we examined the role of p62 in cell protection during cisplatin-induced oxidative stress, and we found that p62 silencing in HK-2 cells increases apoptosis and reactive oxygen species (ROS) levels, which further indicates the protective role of p62 under oxidative stress and suggests that the cytoprotection 62 mediated is in part by regulating autophagic activity or the Keap1-Nrf2 signalling pathway. Taken together, our results have demonstrated a reciprocal regulation of p62, autophagy and the Keap1-Nrf2 signalling pathway under oxidative stress, which may be a potential therapeutic target against AKI.