Conclusion
Our findings suggested that trehalose induced autophagy to alleviate cisplatin-induced chronic kidney injury by targeting the mTOR-dependent TFEB signaling pathway.
Methods
Firstly, we measured the role of autophagy in cisplatin-induced injury models both in vivo and in vitro by western blot and immunofluorescence staining, combined with transcriptomics. Then, biomedical, cellular, and molecular approaches were utilized to evaluate the potential protective effect of trehalose intervention in regulating autophagy. Mechanistically, we performed this study using proximal tubular epithelial cells-specific transcription factor EB (TFEB) knockout mice and TFEB small-interfering RNA technology to determine whether TFEB deficiency affects the pharmacological effected of trehalose in cisplatin-induced injury models.
Results
Due to the activation of autophagy, trehalose inhibited mitochondrial dysfunction (mitochondrial fragmentation, depolarization, reactive oxygen species) and cellular senescence induced by cisplatin both in vitro and in vivo. Moreover, renal dysfunction, pathological changes and fibrosis were alleviated in CKD mice after trehalose treatment. Mechanistic investigations revealed that trehalose accumulated in lysosomes and inhibited mTORC1 activity, which triggered TFEB and TFEB-mediated autophagy. In addition, siRNA-mediated knockdown of TFEB in HK2 cells or renal proximal tubular epithelial cells-specific (TECs-specific) TFEB deficiency in mice markedly abolished the beneficial effects of trehalose.