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Abstract: PO0349

Intraflagellar Transport Protein 88 Deficiency in Proximal Tubular Cells Exaggerates Cisplatin-Induced Injury by Suppressing Autophagy

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Wang, Shixuan, Augusta University, Augusta, Georgia, United States
  • Dong, Zheng, Augusta University, Augusta, Georgia, United States
Background

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 previously showed that shortening of primary cilia sensitizes cultured kidney tubular cells to cisplatin-induced apoptosis. IFT88 is an essential component for ciliogenesis and maintenance.

Methods

To study the effect of proximal tubule-specific IFT88 ablation on cisplatin-induced acute kidney injury (AKI), we took advantage of conditional IFT88 knockout mice to study how differently cisplatin affected renal function in knockout mice and age- and sex-matched wild type ones. Furthermore, we used cultured cells to examine whether autophagy was involved.

Results

It was found that more severe AKI occurred in IFT88 knockout mouse than controls. Mechanistically, cisplatin stimulated autophagy in kidney tubular cells as an intrinsic protective mechanism. However, renal autophagy was severely impaired in IFT88 knockout mouse. 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.

Conclusion

These results indicate that defective autophagy in IFT88-deficient kidney cells and tissues contributes to the exaggerated AKI following cisplatin exposure.

Funding

  • NIDDK Support