IFT88 deficiency in proximal tubular cells exaggerates cisplatin-induced injury by suppressing autophagy

Shixuan Wang, Shougang Zhuang, Zheng Dong

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Primary cilia are widely regarded as specialized sensors in differentiated cells that have been implicated in the regulation of cell proliferation, differentiation, and viability. We have previously shown that shortening of primary cilia sensitizes cultured kidney tubular cells to cisplatin-induced apoptosis. Intraflagellar transport 88 (IFT88) is an essential component for ciliogenesis and maintenance. Here, we have further examined the effect of proximal tubule-specific IFT88 ablation on cisplatin-induced acute kidney injury (AKI). In this study, more severe AKI occurred in IFT88 knockout mice than age- and sex-matched wild-type mice. Mechanistically, cisplatin stimulated autophagy in kidney tubular cells as an intrinsic protective mechanism. However, renal autophagy was severely impaired in IFT88 knockout mice. In cultured HK-2 cells, cisplatin induced more apoptosis when IFT88 was knocked down. Tat-beclin 1 peptide, a specific autophagy activator, could partially prevent IFT88-associated cell death during cisplatin treatment, although cilium length was not improved significantly. Reexpression of IFT88 partially restored autophagy in IFT88 knockdown cells and suppressed apoptosis during cisplatin treatment. Taken together, these results indicate that defective autophagy in IFT88-deficient kidney cells and tissues contributes to the exaggerated AKI following cisplatin exposure. NEW & NOTEWORTHY Almost every cell has one hair-like, nonmotile antenna projecting from the cell surface, named the primary cilium. In kidney tubular cells, the primary cilium has a protective role, but the underlying mechanism is unclear. This study shows that a short cilium leads to the suppression of autophagy, which is responsible for the heightened injury sensitivity. These findings provide the clues of how to manipulate primary cilium and autophagy to save kidneys.

Original languageEnglish (US)
Pages (from-to)F269-F277
JournalAmerican Journal of Physiology - Renal Physiology
Volume321
Issue number3
DOIs
StatePublished - Aug 30 2021

Keywords

  • Acute kidney injury
  • Autophagy
  • Cisplatin
  • Intraflagellar transport 88
  • Kidney

ASJC Scopus subject areas

  • Physiology
  • Urology

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