title: Repeated administration of low-dose cisplatin in mice induces fibrosis.
abstract: Cisplatin, a chemotherapeutic used for the treatment of solid cancers, has nephrotoxic side effects leading to acute kidney injury (AKI). Cisplatin cannot be given to patients that have comorbidities that predispose them to an increased risk for AKI. Even without these comorbidities, 30% of patients administered cisplatin will develop kidney injury, requiring the oncologist to withhold or reduce the next dose, leading to a less effective therapeutic regimen. Although recovery can occur after one episode of cisplatin-induced AKI, longitudinal studies have indicated that multiple episodes of AKI lead to the development of chronic kidney disease, an irreversible disease with no current treatment. The standard mouse model of cisplatin-induced AKI consists of one high dose of cisplatin (>20 mg/kg) that is lethal to the animal 3 days later. This model does not accurately reflect the dosing regimen patients receive nor does it allow for the long-term study of kidney function and biology. We have developed a repeated dosing model whereby cisplatin is given once a week for 4 wk. Comparison of the repeated dosing model with the standard dosing model demonstrated that inflammatory cytokines and chemokines were induced in the repeated dosing model, but levels of cell death were lower in the repeated dosing model. The repeated dosing model had increased levels of fibrotic markers (fibronectin, transforming growth factor-β, and α-smooth muscle actin) and interstitial fibrosis. These data indicate that the repeated dosing model can be used to study the AKI to chronic kidney disease progression as well as the mechanisms of this progression.
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Cierra N
authors.initials: CN
authors.lastname: Sharp
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Doll
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Tess V
authors.initials: TV
authors.lastname: Dupre
authors.affiliation: Department of Medicine, University of Louisville, Louisville, Kentucky; James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; and.
authors.forename: Parag P
authors.initials: PP
authors.lastname: Shah
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Marimuthu
authors.initials: M
authors.lastname: Subathra
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Deanna
authors.initials: D
authors.lastname: Siow
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky;
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Arteel
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas, Veterans Healthcare System, Little Rock, Arkansas.
authors.forename: Judit
authors.initials: J
authors.lastname: Megyesi
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; Department of Medicine, University of Louisville, Louisville, Kentucky; James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; and.
authors.forename: Levi J
authors.initials: LJ
authors.lastname: Beverly
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky; and leah.siskind@louisville.edu.
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Siskind
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015415:Biomarkers / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D009400:Nephrosclerosis / Q000139:chemically induced* / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D018925:Chemokines; D002945:Cisplatin
keywords: acute kidney injury; chronic kidney disease; cisplatin; fibrosis; nephrotoxicity