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

Theranostics. 2020 Apr 27;10(13):5829-5844. doi: 10.7150/thno.44051. eCollection 2020.

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.

Keywords: acute kidney injury; autophagy; mitochondrial dysfunction; transcription factor EB; trehalose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / physiopathology
  • Animals
  • Apoptosis / drug effects
  • Autophagy / drug effects
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / drug effects
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cells, Cultured
  • China
  • Cisplatin / adverse effects
  • Cisplatin / pharmacology
  • Humans
  • Kidney / metabolism
  • Kidney Tubules, Proximal / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Mitochondrial Diseases / drug therapy
  • Reactive Oxygen Species / metabolism
  • Trehalose / metabolism
  • Trehalose / pharmacology*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Reactive Oxygen Species
  • Tcfeb protein, mouse
  • Trehalose
  • Cisplatin