College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China.
College of Animal Science and Veterinary Medicine, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province 271018, China; Institute of Poultry Science, Shandong Academy of Agricultural Sciences, Jinan, Shandong Province, 250023, China.
J Inorg Biochem. 2018 May;182:184-193. doi: 10.1016/j.jinorgbio.2018.02.015. Epub 2018 Feb 24.
Autophagy and apoptosis are two different biological processes that determine cell fates. We previously reported that autophagy inhibition and apoptosis induction are involved in lead(II)-induced cytotoxicity in primary rat proximal tubular (rPT) cells, but the interplay between them remains to be elucidated. Firstly, data showed that lead(II)-induced elevation of LC3-II protein levels can be significantly modulated by 3-methyladenine or rapamycin; moreover, protein levels of Autophagy-related protein 5 (Atg5) and Beclin-1 were markedly up-regulated by lead(II) treatment, demonstrating that lead(II) could promote the autophagosomes formation in rPT cells. Next, we applied three pharmacological agents and genetic method targeting the early stage of autophagy to validate that enhancement of autophagosomes formation can inhibit lead(II)-induced apoptotic cell death in rPT cells. Simultaneously, lead(II) inhibited the autophagic degradation of rPT cells, while the addition of autophagic degradation inhibitor bafilomycin A1 aggravated lead(II)-induced apoptotic death in rPT cells. Collectively, this study provided us a good model to know about the dynamic process of lead(II)-induced autophagy in rPT cells, and the interplay between autophagy and apoptosis highlights a new sight into the mechanism of lead(II)-induced nephrotoxicity.
自噬和细胞凋亡是决定细胞命运的两种不同的生物学过程。我们之前的研究表明，自噬抑制和细胞凋亡诱导参与了 lead(II)诱导的原代大鼠近端肾小管 (rPT) 细胞毒性，但它们之间的相互作用仍有待阐明。首先，数据表明，lead(II)诱导的 LC3-II 蛋白水平升高可以被 3-甲基腺嘌呤或雷帕霉素显著调节；此外，lead(II)处理后 Autophagy-related protein 5 (Atg5) 和 Beclin-1 的蛋白水平明显上调，表明 lead(II)可以促进 rPT 细胞中的自噬体形成。接下来，我们应用了三种针对自噬早期阶段的药理学试剂和基因方法，验证了增强自噬体形成可以抑制 rPT 细胞中 lead(II)诱导的凋亡细胞死亡。同时，lead(II)抑制了 rPT 细胞的自噬降解，而自噬降解抑制剂巴弗洛霉素 A1 的加入加重了 lead(II)诱导的 rPT 细胞凋亡死亡。总之，这项研究为我们提供了一个很好的模型，以了解 rPT 细胞中 lead(II)诱导的自噬的动态过程，以及自噬和细胞凋亡之间的相互作用凸显了 lead(II)诱导的肾毒性的新机制。
