Activation of TFEB-mediated autophagy by trehalose attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury

Abstract

Aims: Cisplatin, an anticancer drug, always leads to nephrotoxicity by causing mitochondrial dysfunction. As a major mechanism for cellular self-degradation, autophagy has been proven to protect against cisplatin-induced acute kidney injury (AKI). Based on the activation of autophagy induced by trehalose, we aimed to investigate the nephroprotective effects of trehalose on cisplatin-induced AKI and its underlying mechanisms.

Results: Due to the activation of autophagy, mitochondrial dysfunction (mitochondrial fragmentation, depolarization, reactive oxygen species (ROS), and reduced ATP generation) and apoptosis induced by cisplatin were markedly inhibited in trehalose-treated HK2 cells in vitro. Based on the transcriptional regulation role of transcription factor EB (TFEB) in autophagy and lysosome, we characterized trehalose-induced nuclear translocation of TFEB. Furthermore, consistent with trehalose treatment, overexpression of TFEB inhibited cell injury induced by cisplatin. However, the protective effects of trehalose were largely abrogated in tfeb-knockdown cells. In vivo, cisplatin injection resulted in severe kidney dysfunction and histological damage in mice. Trehalose administration activated TFEB-mediated autophagy, alleviated mitochondrial dysfunction and kidney injury in AKI mice.

Innovation and conclusion: Our data suggest that trehalose treatment preserves mitochondria function via activation of TFEB-mediated autophagy and attenuates cisplatin-induced kidney injury.