Wei Miaomiao, Li Zhigui, Yang Zhuo
College of Medicine, Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, 300071, China.
Mol Cell Biochem. 2014 Sep;394(1-2):261-73. doi: 10.1007/s11010-014-2102-7. Epub 2014 Jun 24.
Despite a great deal of recent studies focused on the pivotal role of autophagy in maintaining podocyte energy homeostasis, the mechanisms of autophagy in regulating transcriptional factors under high glucose (HG) condition are not fully understood. Here, we evaluated the effect of HG on nuclear factor-kappa B (NF-κB) signaling and autophagic process. The results showed that HG promoted autophagy in podocytes. Bafilomycin A1 (Baf A1) further enhanced this effect, but 3-methyadenine (3-MA) inhibited it. The proautophagic effects of HG manifested in the form of enhanced podocyte expression of light chain 3 (LC3)-II. In these cells, blockade of NF-κB signal by ammonium pyrrolidinethiocarbamate constrained in effectively reducing LC3-II up-regulation and increasing podocyte apoptosis. Furthermore, the autophagy inhibitors, such as Baf A1 and 3-MA, significantly enhanced HG-induced NF-κB activation and increased apoptosis. Thus, we conclude that the accumulation of autophagosomes results from enhancement of the autophagic flux, but not the blockage of autophagosome-lysosome fusion by HG. We also prove that HG-induced apoptosis, autophagy, and NF-κB signal are in a close crosstalk through a yet undetermined mechanism in podocytes.
尽管最近有大量研究聚焦于自噬在维持足细胞能量稳态中的关键作用，但在高糖（HG）条件下自噬调节转录因子的机制仍未完全阐明。在此，我们评估了HG对核因子-κB（NF-κB）信号通路和自噬过程的影响。结果显示，HG促进足细胞自噬。巴弗洛霉素A1（Baf A1）进一步增强了这种作用，但3-甲基腺嘌呤（3-MA）抑制了它。HG的促自噬作用以足细胞轻链3（LC3）-II表达增强的形式体现。在这些细胞中，用吡咯烷二硫代氨基甲酸铵阻断NF-κB信号可有效抑制LC3-II上调并增加足细胞凋亡。此外，自噬抑制剂，如Baf A1和3-MA，显著增强了HG诱导的NF-κB激活并增加凋亡。因此，我们得出结论，自噬体的积累是自噬通量增强的结果，而非HG对自噬体-溶酶体融合的阻断。我们还证明，HG诱导的凋亡、自噬和NF-κB信号在足细胞中通过一种尚未明确的机制紧密相互作用。
