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.

Subcellular trafficking of tubular MDM2 implicates in acute kidney injury to chronic kidney disease transition during multiple low‐dose cisplatin exposure

“…Consistent with previous publication, 18 our data indicated that CP initially triggers acute tubular injury; however, multiple times of CP injection lead to impaired renal function with tubulointerstitial fibrosis. Consistent with previous publication, 18 our data indicated that CP initially triggers acute tubular injury; however, multiple times of CP injection lead to impaired renal function with tubulointerstitial fibrosis.…”

“…Considering the clinic significance of CP's acute and/or chronic nephrotoxicity; here, we established an AKI-CKD murine model by weekly CP intraperitoneal injection for 2-4 times. Consistent with previous publication, 18 our data indicated that CP initially triggers acute tubular injury; however, multiple times of CP injection lead to impaired renal function with tubulointerstitial fibrosis. These data indicated that the AKI-CKD murine model is successfully set up in the current study.…”

“…[15][16][17][18] More importantly, CP is widely used in clinic due to its high efficiency, and to avoid its nephrotoxicity clinicians usually adopt a multiple low-dose administration. [15][16][17][18] More importantly, CP is widely used in clinic due to its high efficiency, and to avoid its nephrotoxicity clinicians usually adopt a multiple low-dose administration.…”

Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death

“…Recent evidence has shown severe AKI causes abnormal cellular repair and fibrosis, leading to chronic diseases and end stage renal disease (ESRD). AKI is characterized by sudden decline in renal function over a short time period, and it is always induced by hemodynamic, hypoxic, mechanical, and toxic insults [1,2]. Although programmed cell death and inflammation are believed to play roles in the pathophysiological process of AKI, a detailed mechanism and effective therapy are yet to be determined [3,4].…”

Molecular Mechanisms Underlying the Nephrotoxicity of Cisplatin, Lead Acetate and Cyclosporine: Key Roles of Myc and Smad4

“…Renal fibrosis is the final common result in loss of kidney function. TGFβ-Smad signaling has been determined to contribute in nephrotoxicity [60][61][62]. TGFβ signaling pathway plays multiple functions in cytokine-mediated signaling in many cell types, conditioning them for differentiation, survival, apoptosis and fibrosis [63].…”