Date on Senior Honors Thesis

5-2018

Document Type

Senior Honors Thesis

Degree Name

B.A.

Department

Chemistry

Author's Keywords

acute kidney injury; chronic kidney disease; cisplatin; fibrosis; nephrotoxicity

Abstract

Cisplatin is a potent chemotherapeutic; the dose-limiting side effect of this drug is nephrotoxicity, causing acute kidney injury (AKI) in 30% of adult patients. Patients with cisplatin-induced AKI are more likely to develop end stage renal diseases, particularly chronic kidney disease (CKD), which is marked by the development of fibrosis. Currently, there are no therapeutic interventions for cisplatin-induced kidney injury, which may be due to limitations in the mouse model used to study this type of injury. We have previously developed a repeated dosing regimen of cisplatin (mice treated with 7 mg/kg once a week for 4 weeks, mice sacrificed at Day 24). With this dosing regimen, FVB/n background mice survive and develop renal fibrosis indicative of CKD. Commonly, C57BL/6J background mice are utilized to study the nephrotoxic effects of cisplatin on the kidney; however, C57BL/6J mice have been shown to be resistant to renal fibrosis in some models of experimental fibrosis. We wanted to determine if the resistance to the development of renal fibrosis would also be evident with our repeated dosing regimen of cisplatin. Preliminary data have indicated that while FVB/n mice develop fibrosis when treated with 7 mg/kg of cisplatin, C57BL/6J mice do not. We hypothesized that C57BL/6J mice will require a higher dose of cisplatin in order to develop interstitial fibrosis that occurs with repeated dosing of cisplatin. Several techniques were utilized including QRTPCR, IHC, and Western blot analysis to determine the presence of fibrosis in these mice, as well as compare fibrotic and inflammatory markers to FVB/n mice treated with cisplatin. Both strains of mice treated with repeated dosing of cisplatin had a robust inflammatory response and an increase in fibrotic marker levels. These data suggest that C57BL/6J mice are susceptible to the development of renal fibrosis with our repeated dosing model of cisplatin.

Additional Files
Oropilla_G TIP.pdf (944 kB)
Timeline & Research Approvals

Lay Summary

Cisplatin is a potent chemotherapeutic resulting in nephrotoxicity and acute kidney injury. Cisplatin-induced acute kidney injury can also lead to chronic kidney disease. A dose limiting mouse model was developed in order to study this type of injury and the development of fibrosis. Two different mouse strains were studied to analyze genetic differences. The specific aim was to determine if a certain strain of mice, C57BL/6J mice, require a higher dose of cisplatin in order to develop interstitial fibrosis with repeated dosing of cisplatin. With this information, the repeated dosing regimen model could be optimized to be used to model fibrosis in this strain of mouse.

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