Strain differences in susceptibility to cisplatin-induced renal fibrosis

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