Abstract: FR-PO251
5HT-1F Agonist-Mediated Protection Against Cisplatin-Induced Nephrotoxicity Is Abolished in a Murine Model of Lung Cancer
Session Information
- Onconephrology: From AKI to CKD and Everything in Between
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1700 Onconephrology
Authors
- Orwick, Andrew, University of Louisville, Louisville, Kentucky, United States
- Siskind, Leah J., University of Louisville, Louisville, Kentucky, United States
Background
Anti-cancer drug-induced acute kidney injury (AKI) is a persistent problem. Cisplatin is a prominent example of this, 30% of patients develop AKI after a single dose and have an increased risk of chronic kidney disease (CKD). The mechanism driving the AKI to CKD transition in the repeated low-dose cisplatin (RLDC) model is not fully understood. Mitochondrial dysfunction plays a critical role in the transition from AKI to CKD. The role of kidney mitochondrial dynamics/quality control in the RLDC model is currently unknown. Preclinical cisplatin toxicity studies have been completed mostly in mice without cancer. The lack of appropriate preclinical models has led previous research down doomed pathways.
Methods
The objective of this study was to determine if nephroprotective strategies in mice without lung cancer will still protect mice with lung cancer. Eight-week-old B6129 mice with and without lung cancer were administered Cisplatin (7mg/kg) or saline via intraperitoneal (i.p.) injection once a week for four weeks. Following the first dose of cisplatin, mice were administered LY344864 (2mg/kg) or saline 6 days a week via i.p. injection. We pharmacologically induced mitochondrial biogenesis to increase kidney mitochondrial content to determine if this pathway will protect from cisplatin-induced nephrotoxicity.
Results
Stimulating mitochondrial biogenesis increased kidney mitochondrial content and reduced loss of kidney function, kidney injury, inflammation, and development of fibrosis from RLDC in mice without cancer. However, these effects are nullified when the experiment was repeated in mice with subcutaneous lung cancer.
Conclusion
Previous clinical trials on nephroprotective agents have failed, and we propose that poorly representative mouse models may be responsible for misleading preclinical research. Our development of clinically relevant models of cisplatin-induced nephrotoxicity provides a foundation for developing nephroprotective agents that can be used as adjunctive therapy for cancer patients receiving cisplatin.
Funding
- NIDDK Support