Autophagy dysregulation is implicated in cadmium (Cd)-induced nephrotoxicity. The mammalian target of rapamycin complex 1 (mTORC1) is a negative regulator of autophagy, but its role in Cd-induced autophagy inhibition and possible regulatory mechanisms remains poorly understood. In the present study, Cd exposure activated mTORC1 in primary rat proximal tubular (rPT) cells, and two mTORC1 inhibitors (rapamycin and torin 1) were separately utilized to inhibit Cd-induced mTORC1 activation. Data showed that Cd-inhibited autophagic flux was markedly restored by two mTORC1 inhibitors, respectively, as evidenced by immunoblot analysis of autophagy marker proteins and tandem red fluorescent protein-green fluorescent protein-microtubule associated protein light chain 3 (RFP-GFP-LC3) fluorescence microscopy assay. Importantly, Cd exposure triggered the recruitment of mTORC1 onto lysosome membrane assessed by immunofluorescence co-localization analysis, which was obviously inhibited by rapamycin or torin 1. Moreover, Cd-induced lysosomal alkalization, suppressed vacuolar ATPases (V-ATPases) protein levels and impaired lysosomal degradation capacity were markedly reversed by rapamycin or torin 1. In summary, these findings demonstrate that Cd recruits mTORC1 to lysosome membrane to induce its activation, which results in lysosomal dysfunction and resultant autophagy inhibition in rPT cells.

自噬失调与镉 (Cd) 诱导的肾毒性有关。哺乳动物雷帕霉素复合物 1 (mTORC1) 靶标是自噬的负调节因子，但其在 Cd 诱导的自噬抑制中的作用和可能的调节机制仍知之甚少。在本研究中，镉暴露激活了原代大鼠近端肾小管 (rPT) 细胞中的 mTORC1，并且两种 mTORC1 抑制剂（雷帕霉素和 torin 1）分别用于抑制镉诱导的 mTORC1 激活。数据显示，两种 mTORC1 抑制剂分别显着恢复了 Cd 抑制的自噬通量，如自噬标记蛋白和串联红色荧光蛋白 - 绿色荧光蛋白 - 微管相关蛋白轻链 3 (RFP-GFP-LC3) 的免疫印迹分析所证明的荧光显微镜检测。重要的，