Abstract: TH-PO305

Activation of Endoplasmic Reticulum Stress Response by Enhanced Polyamine Catabolism Plays an Important Role in Cisplatin-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Zahedi, Kamyar A., University of Cincinnati, Cincinnati, Ohio, United States
  • Barone, Sharon L., University of Cincinnati, Cincinnati, Ohio, United States
  • Brooks, Marybeth, University of Cincinnati, Cincinnati, Ohio, United States
  • Soleimani, Manoocher, University of Cincinnati, Cincinnati, Ohio, United States
Background

Cisplatinis a commonly used and highly effective chemotherapeutic agent utilized for the treatment of a variety of solid tumors. Despite its effectiveness, cisplatin usage is limited due its nephrotoxic side effects. More than 25% of patients treated with cisplatin develop renal failure and have to discontinue treatment. The expression of enzymes involved in polyamine catabolism, spermidine/spermine N1-acetyltransferase (SSAT) and spermine oxidase (SMOX) increase in the kidneys of mice treated with cisplatin. We hypothesized that enhanced polyamine catabolism contributes to tissue damage in cisplatin acute kidney injury (AKI).

Methods

Using knockout mice and chemical neutralization of toxic products of polyamine degradation, the role of polyamine catabolism in cisplatin AKI was examined.

Results

Deficiency of SSAT, SMOX or neutralization of the toxic products of polyamine degradation, H2O2 and aminopropanal, significantly diminished the severity of cisplatin AKI. In vitro studies demonstrated that the induction of SSAT and elevated polyamine catabolism in cells increases the phosphorylation of eukaryotic translation initiation factor 2a (eIF2a), and enhances the expression of binding immunoglobulin (BiP/GRP78) and CCAAT-enhancer-binding protein homologous protein (CHOP/GADD153). The increased expression of endoplasmic reticulum stress response (ERSR) markers was accompanied by the activation of caspase-3. These results suggest that enhanced polyamine degradation in cisplatin AKI may lead to tubular damage through the induction of ERSR and the consequent onset of apoptosis. In support of the above, we show that the ablation of the SSAT or SMOX gene, as well as the neutralization of polyamine catabolism products modulate the onset of ERSR (e.g. lower BiP and CHOP) and apoptosis (e.g. reduced activated caspase-3).

Conclusion

These studies indicate that enhanced polyamine catabolism and its toxic products are important mediators of ERSR and critical to the pathogenesis of cisplatin AKI.

Funding

  • Veterans Affairs Support