Strain Differences in Susceptibility to Cisplatin-Induced Renal Fibrosis
Grade Level at Time of Presentation
Senior
Major
Chemistry
Minor
Spanish
Institution
University of Louisville
KY House District #
25
KY Senate District #
10
Faculty Advisor/ Mentor
Dr. Leah Siskind, PhD; Cierra Sharp; Mark Doll
Department
Pharmacology and Toxicology
Abstract
Cisplatin is a potent chemotherapeutic; the dose-limiting side effect of this drug is nephrotoxicity, causing acute kidney injury in 30% of patients. This can lead to end stage renal diseases, particularly chronic kidney disease (CKD), which is marked by the development of fibrosis. Currently, there are no therapeutic interventions, which may be due to limitations in the mouse model used to study cisplatin-induced kidney injury. We have previously developed a repeated dosing regimen of cisplatin (mice treated with 7 mg/kg once a week for 4 weeks, mice euthanized at Day 24) in which 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 this resistance 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 would require a higher dose of cisplatin in order to develop interstitial fibrosis that occurs with our repeated dosing of cisplatin. Several techniques were utilized including QRTPCR, IHC, and Western blot analysis to determine the presence of fibrosis in these mice and to compare fibrotic and inflammatory markers to FVB/n mice treated with cisplatin. C57BL/6J mice only developed fibrosis when treated with 9 mg/kg cisplatin, which coincided with a robust inflammatory response. In contrast, FVB/n mice developed fibrosis and had a robust inflammatory response with only 7 mg/kg cisplatin. These data suggest that C57BL/6J mice are susceptible to the development of renal fibrosis with our repeated dosing model of cisplatin but only when treated with a higher dose.
Strain Differences in Susceptibility to Cisplatin-Induced Renal Fibrosis
Cisplatin is a potent chemotherapeutic; the dose-limiting side effect of this drug is nephrotoxicity, causing acute kidney injury in 30% of patients. This can lead to end stage renal diseases, particularly chronic kidney disease (CKD), which is marked by the development of fibrosis. Currently, there are no therapeutic interventions, which may be due to limitations in the mouse model used to study cisplatin-induced kidney injury. We have previously developed a repeated dosing regimen of cisplatin (mice treated with 7 mg/kg once a week for 4 weeks, mice euthanized at Day 24) in which 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 this resistance 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 would require a higher dose of cisplatin in order to develop interstitial fibrosis that occurs with our repeated dosing of cisplatin. Several techniques were utilized including QRTPCR, IHC, and Western blot analysis to determine the presence of fibrosis in these mice and to compare fibrotic and inflammatory markers to FVB/n mice treated with cisplatin. C57BL/6J mice only developed fibrosis when treated with 9 mg/kg cisplatin, which coincided with a robust inflammatory response. In contrast, FVB/n mice developed fibrosis and had a robust inflammatory response with only 7 mg/kg cisplatin. These data suggest that C57BL/6J mice are susceptible to the development of renal fibrosis with our repeated dosing model of cisplatin but only when treated with a higher dose.