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Kidney Week

Abstract: PO0640

Renal Macrophage Infiltration Precedes Macrophage to Myofibroblast Transition and T-Cell Recruitment Following Repeated Low-Dose Cisplatin Treatment

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Sears, Sophia Marie, University of Louisville School of Medicine, Louisville, Kentucky, United States
  • Doll, Mark A., 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 commonly used chemotherapeutic agent with dose-limiting nephrotoxicity. 30% of patients who receive cisplatin develop acute kidney injury (AKI), which significantly increases the risk of developing renal fibrosis and chronic kidney disease (CKD). There are currently no therapies approved to prevent or treat cisplatin-induced kidney injury (CDDP-KI) and fibrosis. Other models of renal fibrosis have demonstrated that macrophages can play a pro-fibrogenic role by differentiating into myofibroblasts, the main effector of fibrotic development. Macrophage to myofibroblast transition (MMT) is proposed to occur when bone marrow derived M2 macrophages undergo chronic TGFβ stimulation. We hypothesize that cisplatin promotes fibrosis and CKD development through stimulating chronic macrophage activity and MMT in the kidney.

Methods

We used a clinically relevant, repeated low dose model of CDDP-KI to characterize the immune response and MMT in the kidney following cisplatin treatment.

Results

Flow cytometric analysis revealed significantly increased numbers of renal infiltration of Ly6C hi inflammatory monocytes and F4/80 lo infiltrating macrophages after four doses of cisplatin. These populations remained elevated above vehicle treated controls after a 6-month age out. At the four dose timepoint, we observed an increase in CD206+ F4/80+ cells and Arg-1 mRNA, indicating M2 polarization. We also identified a population of F4/80+ CD206+ αSMA+ cells present in the kidney, suggesting MMT is occurring. Interestingly, at the 6-month timepoint renal CD4+ and CD8+ T cell populations remained significantly elevated in cisplatin-treated mice compared to vehicle treated controls.

Conclusion

These studies provide insight on how the immune response to CDDP-KI can promote CKD via infiltration of bone marrow derived macrophages and subsequent M2 polarization and MMT. These early events orchestrate an immune response that continues up to 6-months after cisplatin treatment. Therefore, targeting macrophages could be a potential strategy for preventing the AKI to CKD transition triggered by cisplatin.

Funding

  • NIDDK Support