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Kidney Week

Abstract: PO2443

F4/80hi Resident Macrophages Contribute to Cisplatin-Induced Kidney Fibrosis and M2 Polarization in C57BL/6 Mice

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Sears, Sophia Marie, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Vega, Alexis, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Doll, Mark A., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Shah, Parag P., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Beverly, Levi J., University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Siskind, Leah J., University of Louisville School of Medicine, Louisville, Kentucky, United States
Background

Cisplatin is a mainstay in the treatment of many solid-organ cancers. Its therapeutic benefits, however, are hindered by dose-limiting nephrotoxicity. Cisplatin causes acute kidney injury (AKI) in 30% of patients. Development of AKI puts patients at risk for development of fibrosis and chronic kidney disease (CKD). Cisplatin-induced kidney fibrosis can be modeled in rodents using repeated, low doses of cisplatin once a week for four weeks. Understanding the mechanisms that promote fibrosis in this model could improve long-term care of cancer patients who receive cisplatin. Macrophages are known to respond to kidney injury and correlate with progression of fibrosis in CKD patients, indicating they may be key regulators of fibrosis development following kidney insults. We hypothesize that chronic macrophage activity promotes cisplatin-induced kidney fibrosis.

Methods

In this study, we depleted populations of F4/80hi resident macrophages and F4/80lo infiltrating macrophages in C57BL/6 mice using either clodronate encapsulated liposomes or CCR2 genetic knockout, respectively. In parallel with this macrophage depletion, mice were given 4 weekly doses of 9 mg/kg cisplatin. After euthanization, we evaluated kidney function, injury, and fibrosis development.

Results

Our data suggests that F4/80hi resident macrophage depletion ameliorates development of cisplatin-induced fibrosis, as measured by statistically significant decreased collagen deposition and myofibroblast accumulation. In contrast, CCR2 knockout and subsequent F4/80lo infiltrating macrophage depletion did not alter pathological outcomes after cisplatin treatment. Additionally, depletion of resident macrophages, but not infiltrating macrophages, decreased accumulation of CD206+ M2 macrophages in cisplatin treated kidneys.

Conclusion

Taken together, these data suggest that F4/80hi resident macrophages may be key drivers in the development of cisplatin-induced kidney fibrosis and the primary source of M2 macrophages in the kidney. Therefore, kidney resident macrophages represent a possible target for preventing long-term kidney damage associated with cisplatin treatment.

Funding

  • NIDDK Support