Abstract: TH-PO236

TSA Can Induce Autophagy to Protect against Cisplatin-Induced Apoptosis

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Liu, Jing, The Second Xiangya Hospital,Central South University, Changsha, China
  • Livingston, Man J., Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Dong, Zheng, Augusta University Medical College of Georgia, Augusta, United States
Background

HDAC inhibitors have protective effects against tubular cell injury and death in acute kidney injury (AKI). However, the underlying mechanism remains elusive. Autophagy is known to be an important protective mechanism in AKI. Whether HDAC inhibitors regulate autophagy and protect renal tubular cells from injury via autophagy is currently unknown.

Methods

In vitro, rat proximal tubular cells (RPTCs) were treated with cisplatin to induce apoptosis. In vivo, C57BL/6 mice were injected with cisplatin to induce nephrotoxic AKI. The effect of the HDAC inhibitor Trichostatin A (TSA) was examined both in vitro and in vivo models. Chloroquine and kidney proximal tubule-specific ATG7 knockout (PT-ATG7-KO) mice were used to determine the involvement of autophagy in the protective effect of TSA.

Results

In RPTC, cisplatin induced autophagy in 8 hours, which decreased at 20 hours of treatment as indicated by the analysis of LC3 II accumulation and autophagic vesicle formation. At 20 hours, cisplatin induced significant apoptosis in RPTC as indicated by cell morphology and caspase activation. TSA treatment increased autophagy at both 8 and 20 hours of cisplatin treatment. TSA also attenuated cell apoptosis. Importantly, the protective effect of TSA in RPTC was suppressed by the autophagy inhibitor chloroquine and also by ATG7 knockdown. In mice, cisplatin induced autophagy and AKI. TSA further increased autophagy in kidneys during cisplatin treatment and protected against AKI. The protective effect of TSA was suppressed by chloroquine. Moreover, the protective effect of TSA was diminished in PT-ATG7-KO mice.

Conclusion

TSA induces autophagy in renal tubular cells, which accounts for the protective effect of TSA during cisplatin-induced AKI.

Funding

  • NIDDK Support