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Abstract: SA-PO743

Ablation of Polyamine Catabolic Enzymes Protects Against Renal Damage and Fibrosis due to Long-Term Cisplatin Treatment

Session Information

  • CKD: Mechanisms - III
    November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

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

Cisplatin is a highly effective anti-neoplastic agent against a variety of solid tumors; however, complications associated with its use such as nephrotoxicity limit its effectiveness. While cisplatin's main anti-tumor activity is via the formation of DNA adducts and disruption of cell cycle progression, its general toxicity is mediated by the induction of oxidative stress. Enhanced polyamine catabolism, mediated via increased expression and activity of spermidine/spermine N1-acetyltransferase (SAT1) and spermine oxidase (SMOX), and generation of toxic products of polyamine degradation (acrolein, H2O2 and aldehydes) is important in the mediation of acute kidney injury in mice treated with a single high dose of cisplatin (20mg/kg). We hypothesized that the inhibition of polyamine catabolism will reduce the severity of chronic renal injury caused by long-term cisplatin treatment.

Methods

Using a multiple low dose cisplatin (single weekly cisplatin injection of 7mg/kg for 4 weeks) which more closely simulates the course of cisplatin treatment in cancer patients, we examined the effect of inhibition of polyamine catabolism on the severity of renal injury. The onset and severity of renal damage was determined by assessment of renal function (serum creatinine and blood urea nitrogen levels), damage to the tubular epithelium and renal fibrosis.

Results

Treatment of mice with multiple low doses of cisplatin led to renal tubular damage, interstitial fibrosis and deterioration of renal function. This was associated with increased expression of polyamine catabolizing enzymes Sat1 and Smox transcripts. Comparing the effect of multiple low dose cisplatin treatment in wild type (Wt), Smox-KO and Sat1-KO mice revealed that Sat1-KO and Smox-KO mice are significantly protected against renal tubular injury, interstitial fibrosis and loss of renal function.

Conclusion

These studies indicate that: 1) the expression and activity of Smox and Sat1 increase in animals treated with multiple low doses of cisplatin; and 2) the ablation of these genes reduces the severity of renal injury, interstitial fibrosis and loss of renal function. These results suggest that modulating the activity of polyamine catabolic enzymes or neutralizing the toxic products of polyamine catabolism protects against cisplatin-induced chronic renal injury.

Funding

  • Veterans Affairs Support