Aristolochic acid I induced autophagy extenuates cell apoptosis via ERK 1/2 pathway in renal tubular epithelial cells.
Aristolochic acid I induced autophagy extenuates cell apoptosis via ERK 1/2 pathway in renal tubular epithelial cells.
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DOI：
10.1371/journal.pone.0030312
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Zeng Y;Yang X;Wang J;Fan J;Kong Q;Yu X
自噬是一种溶酶体降解途径，对细胞生存和组织内稳态是必不可少的。然而，关于马兜铃酸(AA)肾病自噬的信息有限。在本研究中，我们研究了自噬及其相关信号通路在AAI诱导的肾小管上皮细胞(NRK52E细胞)损伤过程中的作用。结果表明，低剂量AAI(10µM)作用NRK52E细胞3-6小时后，细胞内即可检测到自噬，表现为Lc3-II和Beclin 1蛋白表达上调。在NRK52E细胞中，AAI诱导的自噬小体相关的LC3-II在GFP-LC3转染过程中出现斑点染色，为自噬提供了进一步的证据。然而，直到AAI处理后12小时才检测到细胞凋亡。用Wortmannin或3-甲基腺嘌呤(磷酸肌醇3-激酶的两种抑制剂)阻断自噬，或通过小干扰RNA敲除Beclin 1或ATG7使肾小管细胞对凋亡敏感。AAI处理NRK52E细胞后，细胞外信号调节蛋白1和2(ERK1/2)活性呈时间依赖性增加，但c-jun氨基末端蛋白(JNK)和p38活性无明显变化。药物抑制U0126对ERK1/2的磷酸化导致AAI诱导的自噬减少，并伴随着更多的细胞凋亡。综上所述，我们的研究首次证明，在AAI诱导的肾小管上皮细胞损伤过程中，自噬发生早于凋亡发生。AAI通过ERK1/2途径诱导的自噬可能抑制细胞的凋亡，这可能为AAI诱导的病理状态下的细胞存活提供了一种保护机制。
Autophagy is a lysosomal degradation pathway that is essential for cell survival and tissue homeostasis. However, limited information is available about autophagy in aristolochic acid (AA) nephropathy. In this study, we investigated the role of autophagy and related signaling pathway during progression of AAI-induced injury to renal tubular epithelial cells (NRK52E cells). The results showed that autophagy in NRK52E cells was detected as early as 3–6 hrs after low dose of AAI (10 µM) exposure as indicated by an up-regulated expression of LC3-II and Beclin 1 proteins. The appearance of AAI-induced punctated staining of autophagosome-associated LC3-II upon GFP-LC3 transfection in NRK52E cells provided further evidence for autophagy. However, cell apoptosis was not detected until 12 hrs after AAI treatment. Blockade of autophagy with Wortmannin or 3-Methyladenine (two inhibitors of phosphoinositede 3-kinases) or small-interfering RNA knockdown of Beclin 1 or Atg7 sensitized the tubular cells to apoptosis. Treatment of NRK52E cells with AAI caused a time-dependent increase in extracellular signal-regulated kinase 1 and 2 (ERK1/2) activity, but not c-Jun N-terminal kinase (JNK) and p38. Pharmacological inhibition of ERK1/2 phosphorylation with U0126 resulted in a decreased AAI-induced autophagy that was accompanied by an increased apoptosis. Taken together, our study demonstrated for the first time that autophagy occurred earlier than apoptosis during AAI-induced tubular epithelial cell injury. Autophagy induced by AAI via ERK1/2 pathway might attenuate apoptosis, which may provide a protective mechanism for cell survival under AAI-induced pathological condition.
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影响因子：
19
作者：
Funderburk SF;Wang QJ;Yue Z
通讯作者：
Yue Z
影响因子：
4.8
作者：
Petiot, A;Ogier-Denis, E;Codogno, P
通讯作者：
Codogno, P
马兜铃酸 I 和马兜铃内酰胺 I 对培养肾上皮细胞的毒性
影响因子：
3.2
作者：
Li, Ji;Zhang, Liang;Zhang, Luyong
通讯作者：
Zhang, Luyong
影响因子：
19.6
作者：
Balachandran, P;Wei, F;Pasco, DS
通讯作者：
Pasco, DS
影响因子：
19.6
作者：
Pozdzik, A. A.;Salmon, I. J.;Nortier, J. L.
通讯作者：
Nortier, J. L.