Abstract: SA-PO592
Metabolomic Alterations in a Mouse Model of Cisplatin-Induced AKI
Session Information
- AKI: Other Mechanisms and Cell Cultures
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Lim, Yong Jin (James), Western University , London, Ontario, Canada
- Hartjes, Emily D., Western University , London, Ontario, Canada
- Urquhart, Brad, Western University , London, Ontario, Canada
Background
Cisplatin-induced acute kidney injury (AKI) occurs in approximately 1/3 of patients receiving cisplatin therapy, but the reason why only certain patients develop AKI is unknown. AKI is currently diagnosed by increases in serum creatinine (SCr), but nephrotoxicity develops prior to detectable rises in SCr. Discovery of novel predictive/diagnostic markers of AKI is necessary and may help explain the differential susceptibility of cisplatin patients to AKI. FVB mice have shown greater susceptibility to cisplatin AKI than C57BL/6 mice. These two strains were used to model the variability of cisplatin nephrotoxicity observed in humans. We aim to: 1) Determine the differences in expression of renal transporters and enzymes involved in cisplatin disposition these mouse strains; 2) Investigate metabolic differences between FVB and C57BL/6 mice using metabolomics, with the aim of biomarker discovery.
Methods
FVB and C57BL/6 strains were treated with 15 mg/kg cisplatin or saline by intraperitoneal injection. Mice were sacrificed 1 and 3 days following treatment, and blood, urine, and kidneys were collected. Gene expression was assessed using RT-PCR. Liquid chromatography-mass spectrometry was used for untargeted metabolomics.
Results
Renal expression of transporters Oct2 and Oat1, and metabolizing enzyme Ggt1 were higher (+20%, p<0.05; +38%, p<0.01; +45%, p<0.05) in untreated FVB mice compared to C57BL/6. Principle component analysis (PCA) of plasma and kidney samples from untreated FVB and C57BL/6 showed visual separation based on mouse strain. PCA of day 3 plasma and kidney samples separated cisplatin and saline groups for both strains. Multivariate analysis revealed uremic toxins indoxyl sulfate, phenyl sulfate and p-cresyl sulfate to be altered in cisplatin AKI.
Conclusion
FVB mice exhibited increased expression of various renal transporters and enzymes involved in cisplatin disposition, as compared to C57BL/6. PCA clustering of plasma and kidney samples from untreated mice indicates baseline metabolic differences between the strains, while separation by treatment (saline vs. cisplatin) suggests that cisplatin administration alters the metabolic profile of the mice. Future work will further characterize metabolic changes associated with cisplatin AKI. Our data suggests possible mechanisms why FVB mice are more susceptible to cisplatin AKI compared to C57BL/6 mice.
Funding
- Government Support - Non-U.S.