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.
Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
Ecotoxicol Environ Saf. 2021 Jan 15;208:111743. doi: 10.1016/j.ecoenv.2020.111743. Epub 2020 Dec 7.
Autophagy dysregulation plays a pivotal role in cadmium (Cd)-induced nephrotoxicity. Quercetin (Qu), a flavonoid antioxidant with autophagy-enhancing effect, has protective effect on Cd-induced toxicity, but whether it can prevent Cd-induced nephrotoxicity via restoration of autophagy remains unknown. Here, primary rat proximal tubular (rPT) cells were exposed to Cd and/or Qu in vitro to clarify this issue. Data first showed that Cd-impaired autophagic flux was markedly alleviated by Qu, including decreased levels of autophagy marker proteins and recovery of autophagosome-lysosome fusion targeted for lysosomes. Meanwhile, Cd-induced lysosomal alkalization due to v-ATPases inhibition was prominently recovered by Qu. Accordingly, Qu enhanced Cd-diminished lysosomal degradation capacity and lysosome-related gene transcription levels. Notably, Qu improved Cd-inhibited TFEB nuclear translocation and its gene transcription level. Furthermore, data showed that the restoration of Cd-impaired autophagy-lysosome pathway and resultant alleviation of cytotoxicity by Qu are TFEB-dependent using TFEB gene silencing and overexpression technologies. In summary, these data provide novel evidences that the protective action of Qu against Cd-induced autophagy inhibition is attributed to its restoration of lysosomal dysfunction, which is dependent on TFEB.
自噬失调在镉（Cd）诱导的肾毒性中起着关键作用。槲皮素（Qu）是一种具有增强自噬作用的黄酮类抗氧化剂，对 Cd 诱导的毒性具有保护作用，但它是否可以通过恢复自噬来预防 Cd 诱导的肾毒性尚不清楚。在这里，我们在体外将原代大鼠肾小管（rPT）细胞暴露于 Cd 和/或 Qu 来阐明这个问题。数据首先表明，Qu 显著减轻了 Cd 损害的自噬流，包括自噬标记蛋白水平降低和自噬体-溶酶体融合靶向溶酶体的恢复。同时，Qu 明显恢复了 Cd 诱导的由于 v-ATPases 抑制导致的溶酶体碱化。相应地，Qu 增强了 Cd 降低的溶酶体降解能力和溶酶体相关基因转录水平。值得注意的是，Qu 改善了 Cd 抑制的 TFEB 核易位及其基因转录水平。此外，数据表明，使用 TFEB 基因沉默和过表达技术，Qu 恢复了 Cd 损害的自噬-溶酶体途径，并减轻了细胞毒性，这依赖于 TFEB。
总之，这些数据提供了新的证据，表明 Qu 对 Cd 诱导的自噬抑制的保护作用归因于其对溶酶体功能障碍的恢复，这依赖于 TFEB。
